Isoindolinone inhibitors of the mdm2-p53 interaction having anticancer activity

ABSTRACT

Also provided are pharmaceutical compositions containing the compounds of formula (I), processes for making the compounds and the medical uses of the compounds.

FIELD OF THE INVENTION

The invention relates to new isoindolin-1-one derivatives, topharmaceutical compositions comprising said compounds and to the use ofsaid compounds in the treatment of diseases, e.g. cancer.

RELATED APPLICATIONS

This application is related to United Kingdom patent application number1517217.4 filed 29 Sep. 2015, the contents of which are incorporatedherein by reference in their entirety.

BACKGROUND OF THE INVENTION

The transformation-related protein 53 (TP53) gene encodes a 53 KDaprotein—p53. The tumour suppressor protein p53 reacts to cellularstresses, such as hypoxia, DNA damage and oncogenic activation, via anumber of posttranslational modifications including phosphorylation,acetylation and methylation, and acts as a signalling node in thediverse pathways that become activated. p53 has additional roles inother physiological processes, including autophagy, cell adhesion, cellmetabolism, fertility, and stem cell aging and development.Phosphorylation of p53, resulting from activation of kinases includingATM, CHK1 and 2, and DNA-PK, results in a stabilised andtranscriptionally active form of the protein, thus producing a range ofgene products. The responses to p53 activation include apoptosis,survival, cell-cycle arrest, DNA-repair, angiogenesis, invasion andautoregulation. The specific combination of which, in concert with thecell's genetic background, gives rise to the observed cellular effecti.e. apoptosis, cell-cycle arrest or senescence. For tumour cells, theapoptotic pathway may be favoured due to the loss of tumour suppressorproteins and associated cell cycle checkpoint controls, coupled withoncogenic stress.

Under conditions of stress such as hypoxia and DNA damage it is knownthat the cellular level of the protein p53 increases. p53 is known toinitiate transcription of a number of genes which govern progressionthrough the cell cycle, the initiation of DNA repair and programmed celldeath. This provides a mechanism for the tumour suppressor role of p53evidenced through genetic studies.

The activity of p53 is negatively and tightly regulated by a bindinginteraction with the MDM2 protein, the transcription of which is itselfdirectly regulated by p53. p53 is inactivated when its transactivationdomain is bound by the MDM2 protein. Once inactivated the functions ofp53 are repressed and the p53-MDM2 complex becomes a target forubiquitinylation.

In normal cells the balance between active p53 and inactive MDM2-boundp53 is maintained in an autoregulatory negative feedback loop. That isto say that p53 can activate MDM2 expression, which in turn leads to therepression of p53.

It has been found that inactivation of p53 by mutation is common inaround half of all common adult sporadic cancers. Furthermore, in around10% of tumours, gene amplification and over-expression of MDM2 resultsin the loss of functional p53, thereby allowing malignant transformationand uncontrolled tumour growth.

Inactivation of p53 by a range of mechanisms is a frequent causal eventin the development and progression of cancer. These include inactivationby mutation, targeting by oncogenic viruses and, in a significantproportion of cases, amplification and/or an elevated rate oftranscription of the MDM2 gene resulting in overexpression or increasedactivation of the MDM2 protein. Gene amplification of MDM2 giving riseto overexpression of MDM2 protein has been observed in tumour samplestaken from common sporadic cancers. Overall, around 10% of tumours hadMDM2 amplification, with the highest incidence found in hepatocellularcarcinoma (44%), lung (15%), sarcomas and osteosarcomas (28%), andHodgkin disease (67%) (Danovi et al., Mol. Cell. Biol. 2004, 24,5835-5843, Toledo et al., Nat Rev Cancer 2006, 6, 909-923, Gembarska etal., Nat Med 2012, 18, 1239-1247). Normally, transcriptional activationof MDM2 by activated p53 results in increased MDM2 protein levels,forming a negative feedback loop. The essential nature of p53 regulationby MDM2 and MDMX is demonstrated by gene knockout mouse models. MDM2−/−knockout mice are embryonically lethal around the time of implantation.Lethality is rescued in the double knockout for Mdm2 and Trp53. MDM2inhibits the activity of p53 directly, by binding to and occluding thep53 transactivation domain, and by promoting the proteosomal destructionof the complex, through its E3-ubiquitin ligase activity. In addition,MDM2 is a transcriptional target of p53, and so the two proteins arelinked in an autoregulatory feedback loop, ensuring that p53 activationis transient.

The induction of the p14ARF protein, the alternate reading frame (ARF)product of the p16INK4a locus, is also a mechanism of negativelyregulating the p53-MDM2 interaction. p14ARF directly interacts with MDM2and leads to up-regulation of p53 transcriptional response. Loss ofp14ARF by a homozygous mutation in the CDKN2A (INK4A) gene will lead toelevated levels in MDM2 and, therefore, loss of p53 function and cellcycle control.

Although MDMX shows strong amino acid sequence and structural homologyto MDM2, neither protein can substitute for loss of the other; MDMX nullmice die in utero, whereas MDM2 knockout is lethal during earlyembryogenesis, however both can be rescued by p53 knockout,demonstrating p53-dependence of the lethality. MDMX also binds p53 andinhibits p53-dependent transcription, but unlike MDM2 it is nottranscriptionally activated by p53 and so does not form the sameautoregulatory loop. Furthermore, MDMX has neither E3 ubiquitin ligaseactivity nor a nuclear localisation signal, however it is believed tocontribute to p53 degradation by forming heterodimers with MDM2 andcontributing to MDM2 stabilisation.

The therapeutic rationale for MDM2-p53 inhibition is that a potentinhibitor of the protein-protein interaction will liberate p53 from therepressive control of MDM2, and activate p53 mediated cell death in thetumour. In tumours, selectivity is envisioned to result from p53 sensingpreexisting DNA-damage or oncogenic activation signals that hadpreviously been blocked by the action of MDM2 at normal or overexpressedlevels. In normal cells, p53 activation is anticipated to result inactivation of non-apoptotic pathways and if anything a protective growthinhibition response. In addition due to the non-genotoxic mechanism ofaction for MDM2-p53 inhibitors they are suitable for the treatment ofcancer in particular in the pediatric population.

About 50% of cancers harbour cells in which TP53, the gene that encodesfor p53, is mutated resulting in a loss of the protein's tumoursuppressor function and sometimes even in p53 protein versions that gainnovel oncogenic functions.

Cancers where there is a high level of MDM2 amplification includeliposarcoma (88%), soft tissue sarcoma (20%), osteosarcoma (16%)oesophageal cancer (13%), and certain paediatric malignancies includingB-cell malignancies.

The present invention describes a novel series of compounds whichselectively inhibit the MDM2-p53 interaction and which have anticanceractivity.

SUMMARY OF THE INVENTION

In one aspect, the invention provides a compound of formula (I):

-   -   or a tautomer or a solvate or a pharmaceutically acceptable salt        thereof, wherein:    -   R¹ is independently selected from hydroxy, halogen, nitro,        nitrile, C₁₋₄alkyl, haloC₁₋₄alkyl, hydroxyC₁₋₄alkyl,        C₂₋₆alkenyl, C₁₋₄alkoxy, haloC₁₋₄alkoxy, C₂₋₄alkynyl,        —O_(0,1)—(CR^(x)R^(y))_(v)—CO₂H,        —(CR^(x)R^(y))_(v)—CO₂C₁₋₄alkyl,        —(CR^(x)R^(y))_(v)—CON(C₁₋₄alkyl)₂, —P(═O)(R^(x))₂,        —S(O)_(d)—R^(x), —S(O)_(d)-heterocyclic group with 3 to 6 ring        members and —S(O)_(d)—N(R⁸)₂;    -   R² is selected from hydrogen, C₁₋₄ alkyl, C₂₋₆alkenyl,        hydroxyC₁₋₄alkyl, —(CR^(x)R^(y))_(u)—CO₂H,        —(CR^(x)R^(y))_(u)—CO₂C₁₋₄alkyl, and        —(CR^(x)R^(y))_(u)—CONR^(x)R^(y);    -   s is selected from 0 and 1;    -   R³ is hydrogen or -(A)_(t)-(CR^(x)R^(y))_(q)—X;    -   t is selected from 0 and 1;    -   q is selected from 0, 1 and 2;    -   wherein when R³ is -(A)_(t)-(CR^(x)R^(y))_(q)—X then (i) at        least one of s, t and q is other than 0 and (ii) when t is 0        then s is 1 and q is other than 0;    -   A is a C₃₋₆cycloalkyl group or a heterocyclic group with 3 to 6        ring members, wherein the heterocyclic group comprises one or        more (e.g. 1, 2, or 3) heteroatoms selected from N, O, S and        oxidised forms thereof;    -   X is selected from hydrogen, halogen, —CN, —OR⁹,        —(CH₂)_(v)—CO₂H, —(CH₂)_(v)—CO₂C₁₋₄alkyl, —S(O)_(d)—R^(x),        —C(═O)—C₁₋₄alkyl, —S(O)_(d)—N(H)_(e)(C₁₋₄alkyl)_(2-e),        —NR^(x)R^(y), —NHSO₂R^(x), —NR^(x)COR^(y), and        —C(═O)NR^(x)R^(y);    -   R⁴ and R⁵ are independently selected from halogen, nitrile, C₁₋₄        alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxy and haloC₁₋₄alkoxy;    -   R⁶ and R⁷ are independently selected from hydrogen, C₁₋₆alkyl,        haloC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, hydroxy,        hydroxyC₁₋₆alkyl, —COOC₁₋₆alkyl, —(CH₂)_(j)—O—C₁₋₆alkyl,        —(CH₂)_(j)—O-(hydroxyC₁₋₆alkyl), —C₁₋₆alkyl-NR^(x)R^(y),        —(CR^(x)R^(y))_(p)—CONR^(x)R^(y),        —(CR^(x)R^(y))_(p)—NR^(x)COR^(y),        —(CR^(x)R^(y))_(p)—O—CH₂—CONR^(x)R^(y), heterocyclic group with        3 to 7 ring members, —CH₂-heterocyclic group with 3 to 7 ring        members, —CH₂—O-heterocyclic group with 3 to 7 ring members,        —CH₂—NH-heterocyclic group with 3 to 7 ring members,        —CH₂—N(C₁₋₆alkyl)-heterocyclic group with 3 to 7 ring members,        —C(═O)NH-heterocyclic group with 3 to 7 ring members,        C₃₋₈cycloalkyl, —CH₂—C₃₋₈cycloalkyl, —CH₂—O—C₃₋₈cycloalkyl, and        C₃₋₈cycloalkenyl, wherein said cycloalkyl, cycloalkenyl or        heterocyclic groups may be optionally substituted by one or more        R^(z) groups, and wherein in each instance the heterocyclic        group comprises one or more (e.g. 1, 2, or 3) heteroatoms        selected from N, O, S and oxidised forms thereof;    -   or the R⁶ and R⁷ groups, together with the carbon atom to which        they are attached, can join to form a C₃₋₆cycloalkyl or        heterocyclyl group with 3 to 6 ring members, wherein the        heterocyclic group comprises one or more (e.g. 1, 2, or 3)        heteroatoms selected from N, O, S and oxidised forms thereof,        and wherein said C₃₋₆cycloalkyl and heterocyclyl groups may be        optionally substituted by one or more R^(z) groups;    -   R⁸ and R⁹ are independently selected from hydrogen, C₁₋₆alkyl,        haloC₁₋₆alkyl, hydroxyC₁₋₆alkyl, —(CH₂)_(k)—O—C₁₋₆alkyl,        —(CH₂)_(k)—O-(hydroxyC₁₋₆alkyl), hydroxyC₁₋₆alkoxy,        —(CH₂)_(k)—CO₂C₁₋₆alkyl, —(CH₂)_(k)—CO₂H, —C₁₋₆        alkyl-N(H)_(e)(C₁₋₄alkyl)_(2-e), —(CH₂)_(j)—C₃₋₈cycloalkyl and        —(CH₂)_(j)—C₃₋₈cycloalkenyl;    -   R^(x) and R^(y) are independently selected from hydrogen,        halogen, nitro, nitrile, C₁₋₆alkyl, haloC₁₋₆alkyl, C₂₋₆alkenyl,        C₂₋₆alkynyl, hydroxy, hydroxyC₁₋₆alkyl, C₁₋₆alkoxy,        —(CH₂)_(k)—O—C₁₋₆alkyl, hydroxyC₁₋₆alkoxy, —COOC₁₋₆alkyl,        —N(H)_(e)(C₁₋₄alkyl)_(2-e),        —C₁₋₆alkyl-N(H)_(e)(C₁₋₄alkyl)_(2-e),        —(CH₂)_(k)—C(═O)N(H)_(e)(C₁₋₄alkyl)_(2-e), C₃₋₈cycloalkyl and        C₃₋₈cycloalkenyl;    -   or the R^(x) and R^(y) groups, together with the carbon or        nitrogen atom to which they are attached, can join to form a        C₃₋₆cycloalkyl or saturated heterocyclyl group with 3 to 6 ring        members which may be optionally fused to an aromatic        heterocyclyl group of 3 to 5 ring members;    -   or when on a carbon atom the R^(x) and R^(y) groups can join        together to form a ═CH₂ group;    -   R^(z) is independently selected from halogen, nitro, nitrile,        C₁₋₆alkyl, haloC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, ═O, hydroxy,        hydroxyC₁₋₆alkyl, C₁₋₆alkoxy, —(CH₂)_(k)—O—C₁₋₆alkyl,        hydroxyC₁₋₆alkoxy, —C(═O)C₁₋₆alkyl, —C(═O)C₁₋₆alkyl-OH,        —C(═O)C₁₋₆alkyl-N(H)_(e)(C₁₋₄alkyl)_(2-e),        —C(═O)N(H)_(e)(C₁₋₄alkyl)_(2-e), —(CH₂)_(r)—CO₂C₁₋₆alkyl,        —(CH₂)_(r)—CO₂H, —N(H)_(e)(C₁₋₄alkyl)_(2-e),        —C₁₋₆alkyl-N(H)_(e)(C₁₋₄alkyl)_(2-e), heterocyclyl group with 3        to 6 ring members, heterocyclyl group with 3 to 6 ring members        substituted by —C(═O)C₁₋₄alkyl, heterocyclyl group with 3 to 6        ring members substituted by —C(═O)OC₁₋₄alkyl, heterocyclyl group        with 3 to 6 ring members substituted by        —C(═O)N(H)_(e)(C₁₋₄alkyl)_(2-e), —C(═O)heterocyclyl group with 3        to 6 ring members, C₃₋₈cycloalkyl and C₃₋₈cycloalkenyl, wherein        if R⁷ is pyridine then R^(z) is other then —NH₂;    -   a, j, d, e, n, r and p are independently selected from 0, 1 and        2;    -   k and m are independently selected from 1 and 2;    -   u is selected from 0, 1, 2 and 3; and    -   v and w are independently selected from 0 and 1.

In a further aspect, the invention provides a compound of formula (I):

-   -   or a tautomer or a solvate or a pharmaceutically acceptable salt        thereof, wherein:    -   R¹ is independently selected from hydroxy, halogen, nitro,        nitrile, C₁₋₄alkyl, haloC₁₋₄alkyl, hydroxyC₁₋₄alkyl,        C₂₋₆alkenyl, C₁₋₄alkoxy, haloC₁₋₄alkoxy, C₂₋₄alkynyl,        —(CR^(x)R^(y))_(v)—CO₂H, —(CR^(x)R^(y))_(v)CO₂C₁₋₄alkyl,        —(CR^(x)R^(y))_(v)—CON(C₁₋₄alkyl)₂, —P(═O)(R^(x))₂,        —S(O)_(d)—R^(x), —S(O)_(d)-heterocyclic group with 3 to 6 ring        members and —S(O)_(d)—N(R⁸)₂;    -   R² is selected from hydrogen, C₁₋₄ alkyl, C₂₋₆alkenyl,        hydroxyC₁₋₄alkyl, —(CR^(x)R^(y))_(u)—CO₂H,        —(CR^(x)R^(y))_(u)—CO₂C₁₋₄alkyl, and        —(CR^(x)R^(y))_(u)—CONR^(x)R^(y);    -   s is selected from 0 and 1;    -   R³ is hydrogen or -(A)_(t)-(CR^(x)R^(y))_(q)—X;    -   t is selected from 0 and 1;    -   q is selected from 0, 1 and 2;    -   wherein when R³ is -(A)_(t)-(CR^(x)R^(y))_(q)—X then (i) at        least one of s, t and q is other than 0 and (ii) when t is 0        then s is 1 and q is other than 0;    -   A is a C₃₋₆cycloalkyl group or a heterocyclic group with 3 to 6        ring members, wherein the heterocyclic group comprises one or        more (e.g. 1, 2, or 3) heteroatoms selected from N, O, S and        oxidised forms thereof;    -   X is selected from hydrogen, halogen, —CN, —OR⁹,        —(CH₂)_(v)—CO₂H, —(CH₂)_(v)—CO₂C₁₋₄alkyl, —S(O)_(d)—R^(x),        —C(═O)—C₁₋₄alkyl, —S(O)_(d)—N(H)_(e)(C₁₋₄alkyl)_(2-e),        —NR^(x)R^(y), —NHSO₂R^(x), —NR^(x)COR^(y), and        —C(═O)NR^(x)R^(y);    -   R⁴ and R⁵ are independently selected from halogen, nitrile, C₁₋₄        alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxy and haloC₁₋₄alkoxy;    -   R⁶ and R⁷ are independently selected from hydrogen, C₁₋₆alkyl,        haloC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, hydroxy,        hydroxyC₁₋₆alkyl, —COOC₁₋₆alkyl, —(CH₂)_(j)—O—C₁₋₆alkyl,        —(CH₂)_(j)—O-(hydroxyC₁₋₆alkyl), —C₁₋₆alkyl-NR^(x)R^(y),        —(CR^(x)R^(y))_(p)—CONR^(x)R^(y),        —(CR^(x)R^(y))_(p)—NR^(x)COR^(y),        —(CR^(x)R^(y))_(p)—O—CH₂—CONR^(x)R^(y), heterocyclic group with        3 to 7 ring members, —CH₂-heterocyclic group with 3 to 7 ring        members, —CH₂—O-heterocyclic group with 3 to 7 ring members,        —CH₂—NH-heterocyclic group with 3 to 7 ring members,        —CH₂—N(C₁₋₆alkyl)-heterocyclic group with 3 to 7 ring members,        —C(═O)NH-heterocyclic group with 3 to 7 ring members,        C₃₋₈cycloalkyl, —CH₂—C₃₋₈cycloalkyl, —CH₂—O—C₃₋₈cycloalkyl, and        C₃₋₈cycloalkenyl, wherein said cycloalkyl, cycloalkenyl or        heterocyclic groups may be optionally substituted by one or more        R^(z) groups, and wherein in each instance the heterocyclic        group comprises one or more (e.g. 1, 2, or 3) heteroatoms        selected from N, O, S and oxidised forms thereof;    -   or the R⁶ and R⁷ groups, together with the carbon atom to which        they are attached, can join to form a C₃₋₆cycloalkyl or        heterocyclyl group with 3 to 6 ring members, wherein the        heterocyclic group comprises one or more (e.g. 1, 2, or 3)        heteroatoms selected from N, O, S and oxidised forms thereof,        and wherein said C₃₋₆cycloalkyl and heterocyclyl groups may be        optionally substituted by one or more R^(z) groups;    -   R⁸ and R⁹ are independently selected from hydrogen, C₁₋₆alkyl,        haloC₁₋₆alkyl, hydroxyC₁₋₆alkyl, —(CH₂)_(k)—O—C₁₋₆alkyl,        —(CH₂)_(k)—O-(hydroxyC₁₋₆alkyl), hydroxyC₁₋₆alkoxy,        —(CH₂)_(k)—CO₂C₁₋₆alkyl, —(CH₂)_(k)—CO₂H, —C₁₋₆        alkyl-N(H)_(e)(C₁₋₄alkyl)_(2-e), —(CH₂)_(j)—C₃₋₈cycloalkyl and        —(CH₂)_(j)—C₃₋₈cycloalkenyl;    -   R^(x) and R^(y) are independently selected from hydrogen,        halogen, nitro, nitrile, C₁₋₆alkyl, haloC₁₋₆alkyl, C₂₋₆alkenyl,        C₂₋₆alkynyl, hydroxy, hydroxyC₁₋₆alkyl, C₁₋₆alkoxy,        —(CH₂)_(k)—O—C₁₋₆alkyl, hydroxyC₁₋₆alkoxy, —COOC₁₋₆alkyl,        —N(H)_(e)(C₁₋₄alkyl)_(2-e),        —C₁₋₆alkyl-N(H)_(e)(C₁₋₄alkyl)_(2-e),        —(CH₂)_(k)—C(═O)N(H)_(e)(C₁₋₄alkyl)_(2-e), C₃₋₈cycloalkyl and        C₃₋₈cycloalkenyl;    -   or the R^(x) and R^(y) groups, together with the carbon or        nitrogen atom to which they are attached, can join to form a        C₃₋₆cycloalkyl or saturated heterocyclyl group with 3 to 6 ring        members which may be optionally fused to an aromatic        heterocyclyl group of 3 to 5 ring members;    -   or when on a carbon atom the R^(x) and R^(y) groups can join        together to form a ═CH₂ group;    -   R^(z) is independently selected from halogen, nitro, nitrile,        C₁₋₆alkyl, haloC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, ═O, hydroxy,        hydroxyC₁₋₆alkyl, C₁₋₆alkoxy, —(CH₂)_(k)—O—C₁₋₆alkyl,        hydroxyC₁₋₆alkoxy, —C(═O)C₁₋₆alkyl, —C(═O)C₁₋₆alkyl-OH,        —C(═O)C₁₋₆alkyl-N(H)_(e)(C₁₋₄alkyl)_(2-e),        —C(═O)N(H)_(e)(C₁₋₄alkyl)_(2-e), —(CH₂)_(r)—CO₂C₁₋₆alkyl,        —(CH₂)_(r)—CO₂H, —N(H)_(e)(C₁₋₄alkyl)_(2-e),        —C₁₋₆alkyl-N(H)_(e)(C₁₋₄alkyl)_(2-e), heterocyclyl group with 3        to 6 ring members, heterocyclyl group with 3 to 6 ring members        substituted by —C(═O)C₁₋₄alkyl, heterocyclyl group with 3 to 6        ring members substituted by —C(═O)OC₁₋₄alkyl, heterocyclyl group        with 3 to 6 ring members substituted by        —C(═O)N(H)_(e)(C₁₋₄alkyl)_(2-e), —C(═O)heterocyclyl group with 3        to 6 ring members, C₃₋₈cycloalkyl and C₃₋₈cycloalkenyl, wherein        if R⁷ is pyridine then R^(z) is other then —NH₂;    -   a, j, d, e, n, r and p are independently selected from 0, 1 and        2;    -   k and m are independently selected from 1 and 2;    -   u is selected from 0, 1, 2 and 3; and    -   v and w are independently selected from 0 and 1.

In further aspects of the invention there is provided a compound offormula (I) for use in the prophylaxis or treatment of a disease orcondition as described herein, methods for the prophylaxis or treatmentof a disease or condition as described herein comprising administeringto a patient a compound of formula (I), pharmaceutical compositionscomprising a compound of formula (I) and processes for the synthesis ofa compound of formula (I).

Definitions

Unless the context indicates otherwise, references to formula (I) in allsections of this document (including the uses, methods and other aspectsof the invention) include references to all other subformula,sub-groups, embodiments and examples as defined herein.

“Potency” is a measure of drug activity expressed in terms of the amountrequired to produce an effect of given intensity. A highly potent drugevokes a larger response at low concentrations. Potency is proportionalto affinity and efficacy. Affinity is the ability of the drug to bind toa receptor. Efficacy is the relationship between receptor occupancy andthe ability to initiate a response at the molecular, cellular, tissue orsystem level.

The term “antagonist” refers to a type of receptor ligand or drug thatblocks or dampens agonist-mediated biological responses. Antagonistshave affinity but no agonistic efficacy for their cognate receptors, andbinding will disrupt the interaction and inhibit the function of anyligand (e.g. endogenous ligands or substrates, an agonist or inverseagonist) at receptors. The antagonism may arise directly or indirectly,and may be mediated by any mechanism and at any physiological level. Asa result, antagonism of ligands may under different circumstancesmanifest itself in functionally different ways. Antagonists mediatetheir effects by binding to the active site or to allosteric sites onreceptors, or they may interact at unique binding sites not normallyinvolved in the biological regulation of the receptor's activity.Antagonist activity may be reversible or irreversible depending on thelongevity of the antagonist-receptor complex, which, in turn, depends onthe nature of antagonist receptor binding.

As used herein, the term “mediated”, as used e.g. in conjunction withMDM2/p53 as described herein (and applied for example to variousphysiological processes, diseases, states, conditions, therapies,treatments or interventions) is intended to operate limitatively so thatthe various processes, diseases, states, conditions, treatments andinterventions to which the term is applied are those in which theprotein plays a biological role. In cases where the term is applied to adisease, state or condition, the biological role played by the proteinmay be direct or indirect and may be necessary and/or sufficient for themanifestation of the symptoms of the disease, state or condition (or itsaetiology or progression). Thus, the protein function (and in particularaberrant levels of function, e.g. over- or under-expression) need notnecessarily be the proximal cause of the disease, state or condition:rather, it is contemplated that the mediated diseases, states orconditions include those having multifactorial aetiologies and complexprogressions in which the protein in question is only partiallyinvolved. In cases where the term is applied to treatment, prophylaxisor intervention, the role played by the protein may be direct orindirect and may be necessary and/or sufficient for the operation of thetreatment, prophylaxis or outcome of the intervention. Thus, a diseasestate or condition mediated by a protein includes the development ofresistance to any particular cancer drug or treatment.

The term “treatment” as used herein in the context of treating acondition i.e. state, disorder or disease, pertains generally totreatment and therapy, whether for a human or an animal (e.g. inveterinary applications), in which some desired therapeutic effect isachieved, for example, the inhibition of the progress of the condition,and includes a reduction in the rate of progress, a halt in the rate ofprogress, amelioration of the condition, diminishment or alleviation ofat least one symptom associated or caused by the condition being treatedand cure of the condition. For example, treatment can be diminishment ofone or several symptoms of a disorder or complete eradication of adisorder.

The term “prophylaxis” (i.e. use of a compound as prophylactic measure)as used herein in the context of treating a condition i.e. state,disorder or disease, pertains generally to the prophylaxis orprevention, whether for a human or an animal (e.g. in veterinaryapplications), in which some desired preventative effect is achieved,for example, in preventing occurrence of a disease or guarding from adisease. Prophylaxis includes complete and total blocking of allsymptoms of a disorder for an indefinite period of time, the mereslowing of the onset of one or several symptoms of the disease, ormaking the disease less likely to occur.

References to the prophylaxis or treatment of a disease state orcondition such as cancer include within their scope alleviating orreducing the incidence e.g. of cancer.

The combinations of the invention may produce a therapeuticallyefficacious effect relative to the therapeutic effect of the individualcompounds/agents when administered separately.

The term ‘efficacious’ includes advantageous effects such as additivity,synergism, reduced side effects, reduced toxicity, increased time todisease progression, increased time of survival, sensitization orresensitization of one agent to another, or improved response rate.Advantageously, an efficacious effect may allow for lower doses of eachor either component to be administered to a patient, thereby decreasingthe toxicity of chemotherapy, whilst producing and/or maintaining thesame therapeutic effect. A “synergistic” effect in the present contextrefers to a therapeutic effect produced by the combination which islarger than the sum of the therapeutic effects of the agents of thecombination when presented individually. An “additive” effect in thepresent context refers to a therapeutic effect produced by thecombination which is larger than the therapeutic effect of any of theagents of the combination when presented individually. The term“response rate” as used herein refers, in the case of a solid tumour, tothe extent of reduction in the size of the tumour at a given time point,for example 12 weeks. Thus, for example, a 50% response rate means areduction in tumour size of 50%. References herein to a “clinicalresponse” refer to response rates of 50% or greater. A “partialresponse” is defined herein as being a response rate of less than 50%.

As used herein, the term “combination”, as applied to two or morecompounds and/or agents, is intended to define material in which the twoor more agents are associated. The terms “combined” and “combining” inthis context are to be interpreted accordingly.

The association of the two or more compounds/agents in a combination maybe physical or non-physical. Examples of physically associated combinedcompounds/agents include:

-   -   compositions (e.g. unitary formulations) comprising the two or        more compounds/agents in admixture (for example within the same        unit dose);    -   compositions comprising material in which the two or more        compounds/agents are chemically/physicochemically linked (for        example by crosslinking, molecular agglomeration or binding to a        common vehicle moiety);    -   compositions comprising material in which the two or more        compounds/agents are chemically/physicochemically co-packaged        (for example, disposed on or within lipid vesicles, particles        (e.g. micro- or nanoparticles) or emulsion droplets);    -   pharmaceutical kits, pharmaceutical packs or patient packs in        which the two or more compounds/agents are co-packaged or        co-presented (e.g. as part of an array of unit doses);

Examples of non-physically associated combined compounds/agents include:

-   -   material (e.g. a non-unitary formulation) comprising at least        one of the two or more compounds/agents together with        instructions for the extemporaneous association of the at least        one compound to form a physical association of the two or more        compounds/agents;    -   material (e.g. a non-unitary formulation) comprising at least        one of the two or more compounds/agents together with        instructions for combination therapy with the two or more        compounds/agents;    -   material comprising at least one of the two or more        compounds/agents together with instructions for administration        to a patient population in which the other(s) of the two or more        compounds/agents have been (or are being) administered;    -   material comprising at least one of the two or more        compounds/agents in an amount or in a form which is specifically        adapted for use in combination with the other(s) of the two or        more compounds/agents.

As used herein, the term “combination therapy” is intended to definetherapies which comprise the use of a combination of two or morecompounds/agents (as defined above). Thus, references to “combinationtherapy”, “combinations” and the use of compounds/agents “incombination” in this application may refer to compounds/agents that areadministered as part of the same overall treatment regimen. As such, theposology of each of the two or more compounds/agents may differ: eachmay be administered at the same time or at different times. It willtherefore be appreciated that the compounds/agents of the combinationmay be administered sequentially (e.g. before or after) orsimultaneously, either in the same pharmaceutical formulation (i.e.together), or in different pharmaceutical formulations (i.e.separately). Simultaneously in the same formulation is as a unitaryformulation whereas simultaneously in different pharmaceuticalformulations is non-unitary. The posologies of each of the two or morecompounds/agents in a combination therapy may also differ with respectto the route of administration.

As used herein, the term “pharmaceutical kit” defines an array of one ormore unit doses of a pharmaceutical composition together with dosingmeans (e.g. measuring device) and/or delivery means (e.g. inhaler orsyringe), optionally all contained within common outer packaging. Inpharmaceutical kits comprising a combination of two or morecompounds/agents, the individual compounds/agents may unitary ornon-unitary formulations. The unit dose(s) may be contained within ablister pack. The pharmaceutical kit may optionally further compriseinstructions for use.

As used herein, the term “pharmaceutical pack” defines an array of oneor more unit doses of a pharmaceutical composition, optionally containedwithin common outer packaging. In pharmaceutical packs comprising acombination of two or more compounds/agents, the individualcompounds/agents may unitary or non-unitary formulations. The unitdose(s) may be contained within a blister pack. The pharmaceutical packmay optionally further comprise instructions for use.

The term ‘optionally substituted’ as used herein refers to a group whichmay be unsubstituted or substituted by a substituent as herein defined.

The prefix “C_(x-y)” (where x and y are integers) as used herein refersto the number of carbon atoms in a given group. Thus, a C₁₋₆ alkyl groupcontains from 1 to 6 carbon atoms, a C₃₋₆ cycloalkyl group contains from3 to 6 carbon atoms, a C₁₋₄ alkoxy group contains from 1 to 4 carbonatoms, and so on.

The term ‘halo’ or ‘halogen’ as used herein refers to fluorine,chlorine, bromine or iodine, in particular fluorine or chlorine.

Each and every hydrogen in the compound (such as in an alkyl group orwhere referred to as hydrogen) includes all isotopes of hydrogen, inparticular ¹H and ²H (deuterium).

The term ‘oxo’ as used herein refers to the group ═O.

The term ‘C₁₋₄alkyl’ as used herein as a group or part of a group refersto a linear or branched saturated hydrocarbon group containing from 1 to4 carbon atoms respectively. Examples of such groups include methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert butyl andthe like.

The term ‘C₂₋₄alkenyl’ or ‘C₂₋₆alkenyl’ as used herein as a group orpart of a group refers to a linear or branched hydrocarbon groupcontaining from 2 to 4, or 2 to 6 carbon atoms, respectively, andcontaining a carbon carbon double bond. Examples of such groups includeC₃₋₄alkenyl or C₃₋₆alkenyl groups, such as ethenyl (vinyl), 1-propenyl,2-propenyl (allyl), isopropenyl, butenyl, buta-1,4-dienyl, pentenyl, andhexenyl.

The term ‘C₂₋₄alkynyl’ or ‘C₂₋₆alkynyl’ as used herein as a group orpart of a group refers to a linear or branched hydrocarbon group havingfrom 2 to 4 or 2 to 6 carbon atoms, respectively, and containing acarbon carbon triple bond. Examples of such groups include C₃₋₄alkynylor C₃₋₆alkynyl groups such as ethynyl and 2 propynyl (propargyl) groups.

The term ‘C₁₋₄alkoxy’ as used herein as a group or part of a grouprefers to an —O—C₁₋₄alkyl group wherein C₁₋₄alkyl is as defined herein.Examples of such groups include methoxy, ethoxy, propoxy, butoxy, andthe like.

The term ‘C₃₋₆cycloalkyl’ as used herein refers to a saturatedmonocyclic hydrocarbon ring of 3 to 6 carbon atoms. Examples of suchgroups include cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl andthe like.

The term ‘C₃₋₆cycloalkenyl’ as used herein refers to a partiallysaturated monocyclic hydrocarbon ring of 3 to 6 carbon atoms having oneor more (usually one) carbon carbon double bond(s). Examples of suchgroups include cyclopentenyl, cyclohexenyl, and cyclohexadienyl.

The term ‘hydroxyC₁₋₄alkyl’ as used herein as a group or part of a grouprefers to a C₁₋₄alkyl group as defined herein wherein one or more (e.g.1, 2 or 3) than one hydrogen atom is replaced with a hydroxyl group. Theterm ‘hydroxyC₁₋₄alkyl’ therefore includes monohydroxyC₁₋₄ alkyl, andalso polyhydroxyC₁₋₄ alkyl. There may be one, two, three or morehydrogen atoms replaced with a hydroxyl group, so the hydroxyC₁₋₄alkylmay have one, two, three or more hydroxyl groups. Examples of suchgroups include hydroxymethyl, hydroxyethyl, hydroxypropyl and the like.

The term ‘haloC₁₋₄alkyl’ as used herein as a group or part of a grouprefers to a C₁₋₄alkyl group as defined herein wherein one or more (e.g.1, 2 or 3) than one hydrogen atom is replaced with a halogen. The term‘haloC₁₋₄alkyl’ therefore includes monohaloC₁₋₄alkyl and alsopolyhaloC₁₋₄alkyl. There may be one, two, three or more hydrogen atomsreplaced with a halogen, so the haloC₁₋₄alkyl may have one, two, threeor more halogens. Examples of such groups include fluoroethyl,fluoromethyl, difluoromethyl, trifluoromethyl or trifluoroethyl and thelike.

The term ‘haloC₁₋₄alkoxy’ as used herein as a group or part of a grouprefers to a —O—C₁₋₄alkyl group as defined herein wherein one or more(e.g. 1, 2 or 3) than one hydrogen atom is replaced with a halogen. Theterms ‘haloC₁₋₄alkoxy’ therefore include monohaloC₁₋₄alkoxy, and alsopolyhaloC₁₋₄alkoxy. There may be one, two, three or more hydrogen atomsreplaced with a halogen, so the haloC₁₋₄alkoxy may have one, two, threeor more halogens. Examples of such groups include fluoroethyloxy,difluoromethoxy or trifluoromethoxy and the like.

The term “heterocyclyl group” as used herein shall, unless the contextindicates otherwise, include both aromatic and non-aromatic ringsystems. Thus, for example, the term “heterocyclyl group” include withintheir scope aromatic, non-aromatic, unsaturated, partially saturated andsaturated heterocyclyl ring systems. In general, unless the contextindicates otherwise, such groups may be monocyclic or bicyclic(including fused, spiro and bridged bicyclic groups) and may contain,for example, 3 to 12 ring members, more usually 5 to 10 ring members.Reference to 4 to 7 ring members includes 4, 5, 6 or 7 atoms in the ringand reference to 4 to 6 ring members include 4, 5, or 6 atoms in thering. Examples of monocyclic groups are groups containing 3, 4, 5, 6, 7and 8 ring members, more usually 3 to 7, or 4 to 7 and preferably 5, 6or 7 ring members, more preferably 5 or 6 ring members. Examples ofbicyclic groups are those containing 8, 9, 10, 11 and 12 ring members,and more usually 9 or 10 ring members. The heterocyclyl groups can beheteroaryl groups having from 5 to 12 ring members, more usually from 5to 10 ring members. Where reference is made herein to a heterocyclylgroup, the heterocyclyl ring can, unless the context indicatesotherwise, be optionally substituted i.e. unsubstituted or substituted,by one or more (e.g. 1, 2, 3, or 4 in particular one or two)substituents as defined herein.

The heterocyclyl group can be, for example, a five membered or sixmembered monocyclic ring or a bicyclic structure formed from fused fiveand six membered rings or two fused six membered rings, or two fusedfive membered rings. Each ring may contain up to five heteroatomsparticularly selected from nitrogen, sulfur and oxygen and oxidisedforms of nitrogen or sulfur. Particularly the heterocyclyl ring willcontain up to 4 heteroatoms, more particularly up to 3 heteroatoms, moreusually up to 2, for example a single heteroatom. In one embodiment, theheterocyclyl ring will contain one or two heteroatoms selected from N,O, S and oxidised forms of N or S. In one embodiment, the heterocyclylring contains at least one ring nitrogen atom. The nitrogen atoms in theheterocyclyl rings can be basic, as in the case of an imidazole orpyridine, or essentially non-basic as in the case of an indole orpyrrole nitrogen. In general the number of basic nitrogen atoms presentin the heterocyclyl group, including any amino group substituents of thering, will be less than five.

The heterocyclyl groups can be attached via a carbon atom or aheteroatom (e.g. nitrogen). Equally the heterocyclyl groups can besubstituted on a carbon atom or on a heteroatom (e.g. nitrogen).

Examples of five membered aromatic heterocyclyl groups include but arenot limited to pyrrolyl, furanyl, thienyl, imidazolyl, furazanyl,oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl,thiadiazolyl, isothiazolyl, pyrazolyl, triazolyl and tetrazolyl groups.

Examples of six membered aromatic heterocyclic groups include but arenot limited to pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl andtriazinyl.

The term “heteroaryl” is used herein to denote a heterocyclyl grouphaving aromatic character. The term “heteroaryl” embraces polycyclic(e.g. bicyclic) ring systems wherein one or more rings are non-aromatic,provided that at least one ring is aromatic. In such polycyclic systems,the group may be attached by the aromatic ring, or by a non-aromaticring.

Examples of heteroaryl groups are monocyclic and bicyclic groupscontaining from five to twelve ring members, and more usually from fiveto ten ring members.

Examples of five membered heteroaryl groups include but are not limitedto pyrrole, furan, thiophene, imidazole, furazan, oxazole, oxadiazole,oxatriazole, isoxazole, thiazole, thiadiazole, isothiazole, pyrazole,triazole and tetrazole groups.

Examples of six membered heteroaryl groups include but are not limitedto pyridine, pyrazine, pyridazine, pyrimidine and triazine.

A bicyclic heteroaryl group may be, for example, a group selected from:

-   -   a) a benzene ring fused to a 5- or 6-membered ring containing 1,        2 or 3 ring heteroatoms;    -   b) a pyridine ring fused to a 5- or 6-membered ring containing        0, 1, 2 or 3 ring heteroatoms;    -   c) a pyrimidine ring fused to a 5- or 6-membered ring containing        0, 1 or 2 ring heteroatoms;    -   d) a pyrrole ring fused to a 5- or 6-membered ring containing 0,        1, 2 or 3 ring heteroatoms;    -   e) a pyrazole ring fused to a 5- or 6-membered ring containing        0, 1 or 2 ring heteroatoms;    -   f) an imidazole ring fused to a 5- or 6-membered ring containing        0, 1 or 2 ring heteroatoms;    -   g) an oxazole ring fused to a 5- or 6-membered ring containing        0, 1 or 2 ring heteroatoms;    -   h) an isoxazole ring fused to a 5- or 6-membered ring containing        0, 1 or 2 ring heteroatoms;    -   i) a thiazole ring fused to a 5- or 6-membered ring containing        0, 1 or 2 ring heteroatoms;    -   j) an isothiazole ring fused to a 5- or 6-membered ring        containing 0, 1 or 2 ring heteroatoms;    -   k) a thiophene ring fused to a 5- or 6-membered ring containing        0, 1, 2 or 3 ring heteroatoms;    -   l) a furan ring fused to a 5- or 6-membered ring containing 0,        1, 2 or 3 ring heteroatoms;    -   m) a cyclohexyl ring fused to a 5- or 6-membered ring containing        1, 2 or 3 ring heteroatoms; and    -   n) a cyclopentyl ring fused to a 5- or 6-membered ring        containing 1, 2 or 3 ring heteroatoms.

Particular examples of bicyclic heteroaryl groups containing a fivemembered ring fused to another five membered ring include but are notlimited to imidazothiazole (e.g. imidazo[2,1-b]thiazole) andimidazoimidazole (e.g. imidazo[1,2-a]imidazole).

Particular examples of bicyclic heteroaryl groups containing a sixmembered ring fused to a five membered ring include but are not limitedto benzofuran, benzothiophene, benzimidazole, benzoxazole,isobenzoxazole, benzisoxazole, benzothiazole, benzisothiazole,isobenzofuran, indole, isoindole, indolizine, indoline, isoindoline,purine (e.g., adenine, guanine), indazole, pyrazolopyrimidine (e.g.pyrazolo[1,5-a]pyrimidine), triazolopyrimidine (e.g.[1,2,4]triazolo[1,5-a]pyrimidine), benzodioxole, imidazopyridine andpyrazolopyridine (e.g. pyrazolo[1,5-a]pyridine) groups.

Particular examples of bicyclic heteroaryl groups containing two fusedsix membered rings include but are not limited to quinoline,isoquinoline, chroman, thiochroman, isochroman, chromene, isochromene,benzodioxan, quinolizine, benzoxazine, pyridopyridine, quinoxaline,quinazoline, cinnoline, phthalazine, naphthyridine and pteridine groups.

Examples of polycyclic heteroaryl groups containing an aromatic ring anda non-aromatic ring include, tetrahydroisoquinoline,tetrahydroquinoline, dihydrobenzthiophene, dihydrobenzofuran,2,3-dihydro-benzo[1,4]dioxine, benzo[1,3]dioxole,4,5,6,7-tetrahydrobenzofuran, tetrahydrotriazolopyrazine (e.g.5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine), chroman,thiochroman, isochroman, chromene, isochromene, benzodioxan,benzoxazine, benzodiazepine, and indoline groups.

A nitrogen-containing heteroaryl ring must contain at least one ringnitrogen atom. The nitrogen-containing heteroaryl ring can be N-linkedor C-linked. Each ring may, in addition, contain up to about four otherheteroatoms particularly selected from nitrogen, sulfur and oxygen.Particularly the heteroaryl ring will contain up to 3 heteroatoms, forexample 1, 2 or 3, more usually up to 2 nitrogens, for example a singlenitrogen. The nitrogen atoms in the heteroaryl rings can be basic, as inthe case of an imidazole or pyridine, or essentially non-basic as in thecase of an indole or pyrrole nitrogen. In general the number of basicnitrogen atoms present in the heteroaryl group, including any aminogroup substituents of the ring, will be less than five.

Examples of nitrogen-containing heteroaryl groups include, but are notlimited to, monocyclic groups such as pyridyl, pyrrolyl, imidazolyl,oxazolyl, oxadiazolyl, thiadiazolyl, oxatriazolyl, isoxazolyl,thiazolyl, isothiazolyl, furazanyl, pyrazolyl, pyrazinyl, pyrimidinyl,pyridazinyl, triazinyl, triazolyl (e.g., 1,2,3-triazolyl,1,2,4-triazolyl), tetrazolyl, and bicyclic groups such as quinolinyl,isoquinolinyl, benzimidazolyl, benzoxazolyl, benzisoxazole,benzothiazolyl and benzisothiazole, indolyl, 3H-indolyl, isoindolyl,indolizinyl, isoindolinyl, purinyl (e.g., adenine [6-aminopurine],guanine [2-amino-6-hydroxypurine]), indazolyl, quinolizinyl,benzoxazinyl, benzodiazepinyl, pyridopyridinyl, quinoxalinyl,quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl and pteridinyl.

Examples of nitrogen-containing polycyclic heteroaryl groups containingan aromatic ring and a non-aromatic ring includetetrahydroisoquinolinyl, tetrahydroquinolinyl, and indolinyl.

The term “non-aromatic” embraces, unless the context indicatesotherwise, unsaturated ring systems without aromatic character,partially saturated and saturated heterocyclyl ring systems. The terms“unsaturated” and “partially saturated” refer to rings wherein the ringstructure(s) contains atoms sharing more than one valence bond i.e. thering contains at least one multiple bond e.g. a C═C, C≡C or N═C bond.The term “saturated” refers to rings where there are no multiple bondsbetween ring atoms. Saturated heterocyclyl groups include piperidinyl,morpholinyl, and thiomorpholinyl. Partially saturated heterocyclylgroups include pyrazolinyl, for example pyrazolin-2-yl andpyrazolin-3-yl.

Examples of non-aromatic heterocyclyl groups are groups having from 3 to12 ring members, more usually 5 to 10 ring members. Such groups can bemonocyclic or bicyclic, for example, have 3 to 7 ring members inparticular 4 to 6 ring members. Such groups particularly have from 1 to5 or 1 to 4 heteroatom ring members (more usually 1, 2, or 3 heteroatomring members), usually selected from nitrogen, oxygen and sulfur andoxidised forms thereof. The heterocyclyl groups can contain, forexample, cyclic ether moieties (e.g. as in tetrahydrofuran and dioxane),cyclic thioether moieties (e.g. as in tetrahydrothiophene and dithiane),cyclic amine moieties (e.g. as in pyrrolidine), cyclic amide moieties(e.g. as in pyrrolidone), cyclic thioamides, cyclic thioesters, cyclicureas (e.g. as in imidazolidin-2-one) cyclic ester moieties (e.g. as inbutyrolactone), cyclic sulfones (e.g. as in sulfolane and sulfolene),cyclic sulfoxides, cyclic sulfonamides and combinations thereof (e.g.thiomorpholine).

Particular examples include morpholinyl, piperidinyl (e.g.piperidin-1-yl, piperidin-2-yl, piperidin-3-yl and piperidin-4-yl),piperidinonyl, pyrrolidinyl (e.g. pyrrolidin-1-yl, pyrrolidin-2-yl andpyrrolidin-3-yl), pyrrolidonyl, azetidinyl, pyranyl (2H-pyran or4H-pyran), dihydrothienyl, dihydropyranyl, dihydrofuranyl,dihydrothiazolyl, tetrahydrofuranyl, tetrahydrothienyl, dioxanyl, oxanyl(also known as tetrahydropyranyl) (e.g. oxan-4-yl), imidazolinyl,imidazolidinonyl, oxazolinyl, thiazolinyl, pyrazolin-2-yl,pyrazolidinyl, piperazinonyl, piperazinyl, and N-alkyl piperazines suchas N-methyl piperazinyl. In general, typical non-aromatic heterocyclylgroups include saturated groups such as piperidinyl, pyrrolidinyl,azetidinyl, morpholinyl, piperazinyl and N-alkyl piperazines such asN-methyl piperazinyl.

The terms “oxan” and “oxanyl” as used herein refer to the group:

which may also be referred to as “tetrahydropyran” ortetrahydropyranyl”.

In a nitrogen-containing non-aromatic heterocyclyl ring the ring mustcontain at least one ring nitrogen atom. The nitrogen-containingheterocyclyl ring can be N-linked or C-linked. The heterocylic groupscan contain, for example, cyclic amine moieties (e.g. as inpyrrolidinyl), cyclic amides (such as a pyrrolidinonyl, piperidinonyl orcaprolactamyl), cyclic sulfonamides (such as an isothiazolidinyl1,1-dioxide, [1,2]thiazinanyl 1,1-dioxide or [1,2]thiazepanyl1,1-dioxide) and combinations thereof.

Particular examples of nitrogen-containing non-aromatic heterocyclylgroups include aziridinyl, morpholinyl, thiomorpholinyl, piperidinyl(e.g. piperidin-1-yl, piperidin-2yl, piperidin-3-yl and piperidin-4-yl),pyrrolidinyl; (e.g. pyrrolidin-1-yl, pyrrolidin-2-yl andpyrrolidin-3-yl), pyrrolidonyl, dihydrothiazolyl, imidazolinyl,imidazolidinonyl, oxazolinyl, thiazolinyl, 6H-1,2,5-thiadiazinyl,pyrazolin-2-yl, pyrazolin-3-yl, pyrazolidinyl, piperazinyl, and N-alkylpiperazines such as N-methyl piperazinyl.

The heterocyclyl groups can be polycyclic fused ring systems or bridgedring systems such as the oxa- and aza analogues of bicycloalkanes,tricycloalkanes (e.g. adamantane and oxa-adamantane). For an explanationof the distinction between fused and bridged ring systems, see AdvancedOrganic Chemistry, by Jerry March, 4th Edition, Wiley Interscience,pages 131-133, 1992.

Where, in a definition of a cyclic group or ring, it is stated that thecyclic group contains a certain number of heteroatom ring members, e.g.as in the phrase “a 5 or 6 membered ring containing 0, 1 or 2 nitrogenring members”, this is to be taken as meaning that apart from thecertain number of heteroatom ring members specified, the remaining ringmembers are carbon atoms.

The compound of formula (I) may contain saturated cyclic groups that canbe joined to the rest of the molecule by one or more bonds. When thecyclic group is joined to the rest of the molecule by two or more bonds,these bonds (or two of these bonds) can be made to the same atom(usually a carbon atom) of the ring or different atoms of the ring.Where the bonds are made to the same atom of the ring, this results in acyclic group with a single atom (usually a quaternary carbon) bound totwo groups. In other words, when the compound of formula (I) includes acyclic group that group may either be linked to the rest of the moleculeby a bond or the cyclic group and the rest of the molecule can have anatom in common e.g. a spiro compound.

The heterocyclyl group can each be unsubstituted or substituted by oneor more (e.g. 1, 2 or 3) substituent groups. For example, heterocyclylor carbocyclyl groups can be unsubstituted or substituted by 1, 2, 3 or4 substituents and particularly it is unsubstituted or has 1, 2 or 3substituents as defined herein. Where the cyclic group is saturatedthere may be 2 substituents joined to the same carbon (where thesubstituents are the same so called geminal or ‘gem’ disubstitution).

A combination of substituents is permissible only if such as combinationresults in a stable or chemically feasible compound (i.e. one that isnot substantially altered when kept at 40° C. or less for at least aweek).

The various functional groups and substituents making up the compoundsof the invention are particularly chosen such that the molecular weightof the compound of the invention does not exceed 1000. More usually, themolecular weight of the compound will be less than 750, for example lessthan 700, or less than 650, or less than 600, or less than 550. Moreparticularly, the molecular weight is less than 525 and, for example, is500 or less.

DETAILED DESCRIPTION OF THE INVENTION

The invention provides a compound of formula (I):

or a tautomer or a solvate or a pharmaceutically acceptable saltthereof, wherein Het, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, a, m, n and s are asdefined herein.

The compounds of the formula (I) have a chiral centre, marked below witha “*”:

The compounds of formula (I) include a stereocentre at the positionindicated (referred to herein as (3)) and are chiral non-racemic.Compounds of formula (I) have the stereochemistry shown by the hashedand solid wedged bonds and this stereoisomer predominates.

Typically, at least 55% (e.g. at least 60%, 65%, 70%, 75%, 80%, 85%, 90%or 95%) of the compound of the formula (I) is present as the shownstereoisomer. In one general embodiment, 97% (e.g. 99%) or more (e.g.substantially all) of the total amount of the compound of the formula(I) may be present as a single stereoisomer.

The compounds may also include one or more further chiral centres (e.g.in the —CR⁶R⁷OH group and/or in the R³ group and/or in the —CHR² group).

Typically, the compound of formula (I) has an enantiomeric excess of atleast 10% (e.g. at least 20%, 40%, 60%, 80%, 85%, 90% or 95%). In onegeneral embodiment, the compound of formula (I) has an enantiomericexcess of 97% (e.g. 99%) or more.

For the purposes of this section the isoindolin-1-one ring is numberedas followed:

Compounds are named in accordance with protocols utilized by chemicalnaming software packages.

R¹ and n

R¹ is the substituent(s) on the phenyl group bonded to —CHR²—.

n is 0, 1, 2 or 3. In other words, the phenyl group bonded to —CHR²—group may have 0, 1, 2 or 3 substituents R¹.

In one embodiment n is 1, 2 or 3. In one embodiment n is 1 or 2. Inanother embodiment n is 1.

When n is 2 or 3 (i.e. the phenyl group bonded to —CHR²— group issubstituted with more than one R¹) the substituents R¹ may be the sameor different (i.e. are independently selected from the definitions ofR¹).

R¹ may be attached at the ortho (or o-), meta (or m-) or para (or p-)position of the phenyl group, wherein the position is defined relativeto the point of attachment of the phenyl group to the group —CHR²—.

R¹ is independently selected from hydroxy, halogen, nitro, nitrile,C₁₋₄alkyl, haloC₁₋₄alkyl, hydroxyC₁₋₄alkyl, C₂₋₆alkenyl, C₁₋₄alkoxy,haloC₁₋₄alkoxy, C₂₋₄alkynyl, —O_(0,1)—(CR^(x)R^(y))_(v)—CO₂H,—(CR^(x)R^(y))_(v)—CO₂C₁₋₄alkyl, —(CH₂)_(v)—CON(C₁₋₄alkyl)₂,—P(═O)(R^(x))₂, —S(O)_(d)—R^(x), —S(O)_(d)-heterocyclic group with 3 to6 ring members and —S(O)_(d)—N(R⁸)₂.

R¹ is independently selected from hydroxy, halogen, nitro, nitrile,C₁₋₄alkyl, haloC₁₋₄alkyl, hydroxyC₁₋₄alkyl, C₂₋₆alkenyl, C₁₋₄alkoxy,haloC₁₋₄alkoxy, C₂₋₄alkynyl, —O_(0,1)—(CH₂)_(v)—CO₂H,—(CH₂)_(v)—CO₂C₁₋₄alkyl, —(CH₂)_(v)—CON(C₁₋₄alkyl)₂, —P(═O)(R^(x))₂,—S(O)_(d)—R^(x), —S(O)_(d)-heterocyclic group with 3 to 6 ring membersand —S(O)_(d)—N(R⁸)₂.

R¹ is independently selected from hydroxy, halogen, nitro, nitrile,C₁₋₄alkyl, haloC₁₋₄alkyl, hydroxyC₁₋₄alkyl, C₂₋₆alkenyl, C₁₋₄alkoxy,haloC₁₋₄alkoxy, C₂₋₄alkynyl, —(CH₂)_(v)—CO₂H, —(CH₂)_(v)—CO₂C₁₋₄alkyl,—(CH₂)_(v)—CON(C₁₋₄alkyl)₂, —P(═O)(R^(x))₂, —S(O)_(d)—R^(x),—S(O)_(d)-heterocyclic group with 3 to 6 ring members and—S(O)_(d)—N(R⁸)₂.

In one embodiment, R¹ is independently selected from halogen, hydroxy,nitrile, C₁₋₄alkyl, C₂₋₄alkynyl, or C₁₋₄alkoxy, for example R¹ isindependently selected from chloro, hydroxy, nitrile, methyl or methoxy.

In one embodiment R¹ is independently selected from halogen (e.g.chloro), C₁₋₄alkyl (e.g. methyl), C₁₋₄alkoxy (e.g. methoxy),—O_(0,1)—(CR^(x)R^(y))_(v)—CO₂H (e.g. —CO₂H, —(CH₂)—CO₂H,—(C(CH₃)₂)—CO₂H, or —O(CH₂)—CO₂H) or —S(O)_(d)—R^(x) (e.g. SO₂CH₃).

In one embodiment R¹ is O_(0,1)—(CR^(x)R^(y))_(v)—CO₂H in particular—CO₂H, —(CH₂)—CO₂H, —(C(CH₃)₂)—CO₂H, or —O(CH₂)—CO₂H), such as—(C(CH₃)₂)—CO₂H.

In one embodiment, R¹ is chloro or nitrile, in particular chloro.

In one embodiment, R¹ is nitro (e.g. p-NO₂).

In one embodiment, R¹ is nitro at the ortho or meta position.

In one embodiment, R¹ is independently selected from hydroxy, halogen,nitrile, C₁₋₄alkyl, haloC₁₋₄alkyl, hydroxyC₁₋₄alkyl, C₂₋₆alkenyl,C₁₋₄alkoxy, haloC₁₋₄alkoxy, C₂₋₄alkynyl, —(CH₂)_(v)—CO₂H,—(CH₂)_(v)—CO₂C₁₋₄alkyl, —(CH₂)_(v)—CON(C₁₋₄alkyl)₂, —P(═O)(R^(x))₂,—S(O)_(d)—C₁₋₆alkyl, —S(O)_(d)-heterocyclic group with 3 to 6 ringmembers and —S(O)_(d)—N(R⁸)₂.

In another embodiment, n is 1 and R¹ is chloro or nitrile.

In another embodiment, n is 1 and R¹ is chloro.

In another embodiment, n is 1 and R¹ is nitrile.

In one embodiment, one of the R¹ groups or the R¹ group (where n=1) isat the para-position (i.e. para to the point of attachment of the phenylring). In one embodiment n is 1 and R¹ is p-chloro or p-nitrile.

In one embodiment, n is 1 and R¹ is halogen (e.g. Cl or F), nitrile,C₁₋₄alkoxy (e.g. —OCH₃) or C₁₋₄alkyl (e.g. —CH₃).

In one embodiment, R¹ is —S(O)_(d)—C₁₋₆alkyl, or —S(O)_(d)-heterocyclicgroup with 3 to 6 ring members and —S(O)_(d)—N(R⁸)₂. In one embodiment,R¹ is —S—C₁₋₆alkyl, —S(O)—C₁₋₆alkyl, —S(O)₂—C₁₋₆alkyl,—S(O)_(d)-heterocyclic group with 3 to 6 ring members or—S(O)_(d)—N(C₁₋₆alkyl)₂.

In another embodiment, R¹ is —S—CH₃, —S(O)—CH₃, —S(O)₂—CH₃, or—S(O)₂-morpholinyl. In another embodiment, one or more R¹ is —SO₂CH₃, or—SO₂-heterocyclic group with 6 ring members e.g. —SO₂-(morpholinyl), inparticular —SO₂-(1-morpholinyl).

In one embodiment, R¹ is o-(—S(O)_(d)—C₁₋₄alkyl) oro-(—S(O)_(d)-heterocyclic group with 3 to 6 ring members). In oneembodiment, R¹ is o-S—C₁₋₄alkyl, o-(—S(O)_(d)—C₁₋₄alkyl) oro-(—S(O)_(d)-heterocyclic group with 3 to 6 ring members). In oneembodiment, R¹ is o-(—S(O)₂—CH₃)

In one embodiment, R¹ is —(CH₂)_(u)—CO₂H. In one embodiment, R¹ is—CO₂H. In one embodiment, R¹ is —(CH₂)_(u)—CO₂H at the meta or paraposition. In one embodiment, R¹ is —(CH₂)_(u)—CO₂H at the orthoposition.

In one embodiment, R¹ is independently selected from hydroxy, halogen,nitrile, C₁₋₄alkyl, haloC₁₋₄alkyl, hydroxyC₁₋₄alkyl, C₂₋₆alkenyl,C₁₋₄alkoxy, haloC₁₋₄alkoxy, C₂₋₄alkynyl, —(CH₂)_(v)—CO₂C₁₋₄alkyl,—(CH₂)_(v)—CON(C₁₋₄alkyl)₂, —P(═O)(R^(x))₂, —S(O)_(d)—C₁₋₆alkyl,—S(O)_(d)-heterocyclic group with 3 to 6 ring members and—S(O)_(d)—N(R⁸)₂.

In one embodiment, n is 2. In one embodiment when n is 2, the phenylgroup is substituted with (i) o-(—S(O)_(d)—C₁₋₄alkyl) oro-(—S(O)_(d)-heterocyclic group with 3 to 6 ring members) and (ii)halogen (e.g. Cl or F), nitrile, or C₁₋₄ alkyl, in particular chloro,nitrile or methyl.

In one embodiment, n is 2 and R¹ is (i) —SO₂CH₃ and (ii) chloro.

In one embodiment n is 2 and R¹ is (i) —SO₂CH₃ and (ii) chloro, nitrileor methyl.

In one embodiment, n is 2 and R¹ is (i) —CO₂H and (ii) chloro.

In one embodiment n is 2 and R¹ is (i) —CO₂H and (ii) chloro, ornitrile.

In one embodiment, when n is 2, the phenyl group bonded to —CHR²— issubstituted with (i) hydroxyl and (ii) halogen (e.g. Cl or F), ornitrile, in particular chloro, or nitrile.

In one embodiment, the phenyl group bonded to —CHR²— and R¹ form agroup:

wherein in particular, R¹ is halogen (for example chloro), nitrile orC₁₋₄alkyl (for example —CH₃) and R^(x) is C₁₋₄alkyl (for example —CH₃).

In one embodiment, the phenyl group bonded to —CHR²— and R¹ form agroup:

wherein in particular, R¹ is C₁₋₄alkyl (for example —CH₃) and R^(x) isC₁₋₄alkyl (for example —CH₃).

In one embodiment when n is 2, the phenyl group is substituted with (i)o-OH or o-CH₂OH and (ii) halogen (e.g. Cl or F), nitrile, or C₁₋₄ alkyl,in particular chloro, or nitrile. In one embodiment, when n is 2, thephenyl group is substituted with (i) hydroxy and (ii) halogen (e.g. Clor F) or nitrile, in particular chloro or nitrile. In one embodiment,when n is 2, the phenyl group is substituted with (i) o-hydroxy and (ii)p-Cl or p-CN (e.g. p-Cl).

In one embodiment, n is 2 and R¹ is fluorine (e.g. at the ortho and parapositions of the phenyl group).

In one embodiment, R¹ is halogen (e.g. Cl or F), C₁₋₄alkynyl (e.g.—C≡CH), nitrile, —(CH₂)_(v)COOH (e.g. —COOH) or SO₂C₁₋₄alkyl (e.g.SO₂CH₃) and n is 1 or 2.

In one embodiment, R¹ is halogen (e.g. Cl), C₁₋₄alkynyl (e.g. —C≡CH),nitrile, hydroxyC₁₋₄alkyl (e.g. CH₂OH), —(CH₂)_(v)COOH (e.g. —COOH),—S(O)_(d)—C₁₋₄alkyl (e.g. SCH₃, SOCH₃, or SO₂CH₃), —SO₂-(1-morpholinyl)or —P(═O)(R^(x))₂, (e.g. —P(═O)(CH₃)₂).

In one embodiment, n is 1 and R¹ is Cl (e.g. p-Cl), CN (e.g. p-CN), orC₂₋₄alkynyl (e.g. p-C₁alkynyl), or n is 2 and (i) R¹ is p-Cl, o-CH₂OH;(ii) p-CN, o-CH₂OH; or (iii) p-Cl, o-COOH, (iv) p-Cl, o-SCH₃, (v) p-Cl,o-S(O)CH₃, (vi) p-Cl, o-SO₂CH₃, (vii) p-Cl, o-SO₂-(1-morpholinyl), or(viii) p-Cl, o-P(O)(CH₃)₂.

In one embodiment, n is 1 and R¹ is Cl (e.g. p-Cl), CN (e.g. p-CN), orC₂₋₄alkynyl (e.g. p-C₁alkynyl).

In one embodiment, n is 2 and (i) R¹ is p-Cl, o-CH₂OH; (ii) p-CN,o-CH₂OH; or (iii) p-Cl, o-COOH, (iv) p-Cl, o-SCH₃, (v) p-Cl, o-S(O)CH₃,(vi) p-Cl, o-SO₂CH₃, (vii) p-Cl, o-SO₂-(1-morpholinyl), or (viii) p-Cl,o-P(O)(CH₃)₂.

In one embodiment n is 1 and R¹ is —Cl, —CN or —OMe (e.g. p-Cl, p-CN orp-OMe). In one embodiment n is 1 and R¹ is —Cl or —CN (e.g. p-Cl orp-CN).

In one embodiment, n is 2. When n is 2, typically the phenyl group issubstituted at the o- and p-positions. In particular, n is 2 and R¹ issubstituted by a p-chloro and either o-(—S(O)_(d)—C₁₋₄alkyl) oro-(—S(O)_(d)-heterocyclic group with 3 to 6 ring members).

In one embodiment, n is 2 and R¹ is o-CO₂H and p-chloro.

In one embodiment, n is 2 and R¹ is o-CO₂H and p-nitrile.

In one embodiment, n is 2 and R¹ is o-CH₂OH and p-chloro.

In one embodiment, n is 2 and R¹ is o-CH₂OH and p-nitrile.

In one embodiment, n is 2 and R¹ is o-OH and p-chloro.

In one embodiment, n is 2 and R¹ is o-OH and p-nitrile.

In one embodiment, n is 2 and R¹ is o-SO₂CH₃ and p-chloro.

In one embodiment n is 2 and R¹ is —SO₂-(1-morpholinyl) and p-chloro.

In one embodiment, R¹ is —O_(0,1)(CR^(x)R^(y))_(v)COOH (e.g. —COOH,—CH₂COOH, —OCH₂COOH or —C(CH₃)₂COOH

In one embodiment, n is 2 and R¹ is p-Cl ando-O_(0,1)(CR^(x)R^(y))_(v)COOH (e.g. —COOH, —CH₂COOH, —OCH₂COOH or—C(CH₃)₂COOH).

In one embodiment, R¹ is halogen (e.g. Cl), hydroxyalkyl (e.g. —CH₂OH),C₁₋₄alkynyl (e.g. —C≡CH), nitrile, —O_(0,1)(CR^(x)R^(y))_(v)COOH (e.g.—COOH, —CH₂COOH, —OCH₂COOH or —C(CH₃)₂COOH) or —SO₂C₁₋₄alkyl (e.g.—SO₂CH₃) and n is 1 or 2.

In one embodiment, R¹ is halogen (e.g. Cl), hydroxyalkyl (e.g. —CH₂OH),C₁₋₄alkynyl (e.g. —C≡CH), nitrile, —(CH₂)_(v)COOH (e.g. —COOH) or—SO₂C₁₋₄alkyl (e.g. —SO₂CH₃) and n is 1 or 2.

In one embodiment, R¹ is independently selected from hydroxy, halogen,nitrile, C₁₋₄alkyl, haloC₁₋₄alkyl, hydroxyC₁₋₄alkyl, C₂₋₆alkenyl,C₁₋₄alkoxy, haloC₁₋₄alkoxy, C₂₋₄alkynyl, —(CH₂)_(v)—CO₂H,—O_(0,1)—(CR^(x)R^(y))_(v)—CO₂C₁₋₄alkyl (e.g. —(CH₂)_(v)—CO₂C₁₋₄alkyl),—(CH₂)_(v)—CON(C₁₋₄alkyl)₂, —P(═O)(R^(x))₂, —S(O)_(d)—C₁₋₆alkyl,—S(O)_(d)-heterocyclic group with 3 to 6 ring members and—S(O)_(d)—N(R⁸)₂.

In one embodiment wherein n is 2, and one R¹ is—O_(0,1)—(CR^(x)R^(y))_(v)—CO₂C₁₋₄alkyl, o-(—S(O)_(d)—C₁₋₄alkyl) oro-(—S(O)_(d)-heterocyclic group with 3 to 6 ring members) and one R¹ ishalogen (e.g. Cl or F), nitrile, or C₁₋₄ alkyl, in particular chloro,nitrile or methyl.

In one embodiment wherein n is 2, and one R¹ is o-(—S(O)_(d)—C₁₋₄alkyl)or o-(—S(O)_(d)-heterocyclic group with 3 to 6 ring members) and one R¹is halogen (e.g. Cl or F), nitrile, or C₁₋₄ alkyl, in particular chloro,nitrile or methyl.

In one embodiment wherein n is 2, and one R¹ is—O_(0,1)—(CR^(x)R^(y))_(v)—CO₂C₁₋₄alkyl, and one R¹ is halogen (e.g. Clor F), nitrile, or C₁₋₄ alkyl, in particular chloro, nitrile or methyl,such as chloro.

R²

R² is selected from hydrogen, C₁₋₄ alkyl, C₂₋₆alkenyl, hydroxyC₁₋₄alkyl,—(CR^(x)R^(y))_(u)—CO₂H, —(CR^(x)R^(y))_(u)—CO₂C₁₋₄alkyl, and—(CR^(x)R^(y))_(u)—CONR^(x)R^(y).

In one embodiment u is selected from 0, 1, or 2. In one embodiment u isselected from 0 or 1.

In one embodiment, R² is selected from hydrogen, C₁₋₄ alkyl,C₂₋₆alkenyl, hydroxyC₁₋₄alkyl and —(CR^(x)R^(y))_(u)—CO₂H. In oneembodiment, R² is selected from hydrogen, C₁₋₄ alkyl, hydroxyC₁₋₄alkyland —(CR^(x)R^(y))_(u)—CO₂H. In one embodiment, R² is selected fromhydrogen, C₁₋₄ alkyl, C₂₋₆alkenyl, and hydroxyC₁₋₄alkyl. In anotherembodiment R² is selected from hydrogen and —(CH₂)_(u)—CO₂H (e.g.—CH₂—CO₂H).

In one embodiment, R² is hydrogen, C₁₋₄ alkyl (e.g. —CH₃),hydroxyC₁₋₄alkyl (e.g. CH₂OH) or —(CH₂)_(u)COOH (e.g. —COOH, —CH₂COOH,—CH₂CH₂—CO₂H, —(CH(CH₃))—CO₂H or —(C(CH₃)₂—CO₂H, such as —COOH,—CH₂COOH, —CH₂CH₂—CO₂H, or —(CH(CH₃))—CO₂H).

In one embodiment, R² is selected from hydrogen, C₁₋₄alkyl, C₂₋₆alkenyl,and hydroxyC₁₋₄alkyl.

In one embodiment, R² is hydrogen, C₁₋₄ alkyl (e.g. —CH₃),hydroxyC₁₋₄alkyl (e.g. CH₂OH) or —(CH₂)_(u)COOH (e.g. —CH₂COOH). In oneembodiment, R² is selected from hydrogen, —CH₃, —CH₂OH, and —CH₂CO₂H.

In one embodiment, R² is selected from hydrogen, —CH₃, —CH₂OH, —CH═CH₂and —CH(OH)CH₂OH.

In one embodiment, R² is selected from hydrogen, —CH₃, —CH₂OH, and—CH₂CO₂H.

In one embodiment, R² is hydrogen or C₁₋₄ alkyl (e.g. —CH₃ or —CH₂CH₃).

In one embodiment, R² is selected from hydrogen, —CH₃ and —CH₂CH₃. Inone embodiment, R² is selected from hydrogen and methyl.

In one embodiment, R² is selected from hydrogen and—(R^(x)R^(y))_(u)—CO₂H (e.g. —COOH, —CH₂COOH, —CH₂CH₂—CO₂H,—(CH(CH₃))—CO₂H and —(C(CH₃)₂—CO₂H).

In one embodiment, R² is —(R^(x)R^(y))_(u)COOH (e.g. —CH₂COOH,—CH₂CH₂—CO₂H, —(CH(CH₃))—CO₂H

or —(C(CH₃)₂—CO₂H).

In one embodiment, R² is hydrogen, C₁₋₄ alkyl (e.g. —CH₃) or—(CH₂)_(u)COOH (e.g. —CH₂COOH, —CH₂CH₂—CO₂H or —(CH(CH₃))—CO₂H).

In one embodiment, R² is hydrogen, C₁₋₄ alkyl (e.g. —CH₃) or—(CH₂)_(u)COOH (e.g. —CH₂COOH).

In one embodiment, R² is —(CR^(x)R^(y))_(u)—CO₂H (e.g. —CH₂—CO₂H).

In another embodiment, R² is selected from —(CH(CH₃))—CO₂H and—(C(CH₃)₂—CO₂H)

or —(C(CH₃)₂—CO₂H.

In another embodiment, R² is hydrogen and the compound of formula (I) isa compound of formula (Ie) or a tautomer or a solvate or apharmaceutically acceptable salt thereof:

When R² is other than hydrogen, the compound of formula (I) can exist asat least two diastereoisomers:

For the avoidance of doubt, the general formula (I) and all subformulaecover both individual diastereoisomers and mixtures of thediastereoisomers which are related as epimers at the —CHR²⁻group. In oneembodiment the compound of formula I is diastereoisomer 1A or a tautomeror a solvate or a pharmaceutically acceptable salt thereof. In oneembodiment the compound of formula I is diastereoisomer 1B or a tautomeror a solvate or a pharmaceutically acceptable salt thereof.

In one embodiment, the compound is diastereoisomer 1A and R² is selectedfrom:

-   -   i. C₁₋₄ alkyl, C₂₋₆alkenyl, hydroxyC₁₋₄alkyl,        —(R^(x)R^(y))_(u)—CO₂H (e.g. —COOH, —CH₂COOH, —CH₂CH₂—CO₂H,        —(CH(CH₃))—CO₂H and —(C(CH₃)₂—CO₂H), —(CH₂)_(u)—CO₂C₁₋₄alkyl,        and —(CH₂)_(u)—CONR^(x)R^(y); or    -   ii. C₁₋₄ alkyl, C₂₋₆alkenyl, and hydroxyC₁₋₄alkyl.

In one embodiment, the compound is diastereoisomer 1A and R² is selectedfrom:

-   -   i. C₁₋₄ alkyl, C₂₋₆alkenyl, hydroxyC₁₋₄alkyl, —(CH₂)_(u)—CO₂H,        —(CH₂)_(u)—CO₂C₁₋₄alkyl, and —(CH₂)_(u)—CONR^(x)R^(y); or    -   ii. C₁₋₄ alkyl, C₂₋₆alkenyl, and hydroxyC₁₋₄alkyl.

In another embodiment R² is selected from hydrogen and—(R^(x)R^(y))_(u)—CO₂H (e.g. —COOH, —CH₂COOH, —CH₂CH₂—CO₂H,—(CH(CH₃))—CO₂H and —(C(CH₃)₂—CO₂H),

In another embodiment R² is selected from hydrogen and —(CH₂)_(u)—CO₂H(e.g. —CH₂—CO₂H).

In one embodiment, the compound is diastereoisomer 1A and R² is selectedfrom:

-   -   i. —CH₃, —CH₂OH, —CH═CH₂ and —CH(OH)CH₂OH; or    -   ii. C₁₋₄ alkyl (e.g. —CH₃ or —CH₂CH₃); or    -   iii. —CH₃ and —CH₂CH₃.

In one embodiment, the compound is diastereoisomer 1B and R² is selectedfrom:

-   -   i. C₁₋₄ alkyl, C₂₋₆alkenyl, hydroxyC₁₋₄alkyl,        —(R^(x)R^(y))_(u)—CO₂H (e.g. —COOH, —CH₂COOH, —CH₂CH₂—CO₂H,        —(CH(CH₃))—CO₂H and —(C(CH₃)₂—CO₂H), —(CH₂)_(u)—CO₂C₁₋₄alkyl,        and —(CH₂)_(u)—CONR^(x)R^(y); or    -   ii. C₁₋₄ alkyl, C₂₋₆alkenyl, and hydroxyC₁₋₄alkyl.

In one embodiment, the compound is diastereoisomer 1B and R² is selectedfrom:

-   -   i. C₁₋₄ alkyl, C₂₋₆alkenyl, hydroxyC₁₋₄alkyl, —(CH₂)_(u)—CO₂H,        —(CH₂)_(u)—CO₂C₁₋₄alkyl, and —(CH₂)_(u)—CONR^(x)R^(y); or    -   ii. C₁₋₄ alkyl, C₂₋₆alkenyl, and hydroxyC₁₋₄alkyl.

In another embodiment R² is selected from hydrogen and —(CH₂)_(u)—CO₂H(e.g. —CH₂—CO₂H).

In one embodiment, the compound is diastereoisomer 1B and R² is selectedfrom:

-   -   i. —CH₃, —CH₂OH, —CH═CH₂ and —CH(OH)CH₂OH; or    -   ii. C₁₋₄ alkyl (e.g. —CH₃ or —CH₂CH₃); or    -   iii. —CH₃ and —CH₂CH₃.

In another embodiment R² is selected from hydrogen and—(R^(x)R^(y))_(u)—CO₂H (e.g. —COOH, —CH₂COOH, —CH₂CH₂—CO₂H,—(CH(CH₃))—CO₂H and —(C(CH₃)₂—CO₂H),

In one embodiment R² is selected from C₁₋₄ alkyl, hydroxyC₁₋₄alkyl,—(CH₂)_(u)—CO₂H, —(CH₂)_(u)—CO₂C₁₋₄alkyl, and —(CH₂)_(u)—CONR^(x)R^(y)(in particular —CH₂—CO₂H) and the compound is diastereoisomer 1A.

In one embodiment R² is selected from C₁₋₄ alkyl, hydroxyC₁₋₄alkyl,—(CH₂)_(u)—CO₂H, —(CH₂)_(u)—CO₂C₁₋₄alkyl, and —(CH₂)_(u)—CONR^(x)R^(y)(in particular —CH₂—CO₂H) and the compound is diastereoisomer 1B.

In one embodiment R² is hydroxyC₁₋₄alkyl (e.g. —CH₂OH) and the compoundis diastereoisomer 1A.

In one embodiment R² is —(CH₂)_(u)—CO₂H (e.g. —CH₂—CO₂H) and thecompound is diastereoisomer 1A.

In one embodiment R² and the hydrogen on the carbon to which it isattached are ²H (i.e. deuterium).

R³ and s

R³ is hydrogen or -(A)_(t)-(CR^(x)R^(y))_(q)—X;

s is selected from 0 and 1;

t is selected from 0 and 1;

q is selected from 0, 1 and 2;

wherein when R³ is -(A)_(t)-(CR^(x)R^(y))_(q)—X then (i) at least one ofs, t and q is other than 0 and (ii) when t is 0 then s is 1 and q isother than 0;

A is a C₃₋₆cycloalkyl group or a heterocyclic group with 3 to 6 ringmembers, wherein the heterocyclic group comprises one or more (e.g. 1,2, or 3) heteroatoms selected from N, O, S and oxidised forms thereof;

X is selected from hydrogen, halogen, —CN, —OR⁹, —(CH₂)_(v)—CO₂H,—(CH₂)_(v)—CO₂C₁₋₄alkyl, —S(O)_(d)—R^(x), —C(═O)—C₁₋₄alkyl,—S(O)_(d)—N(H)_(e)(C₁₋₄alkyl)_(2-e), —NR^(x)R^(y), —NHSO₂R^(x),—NR^(x)COR^(y), and —C(═O)NR^(x)R^(y);

R⁹ is independently selected from hydrogen, C₁₋₆alkyl, haloC₁₋₆alkyl,hydroxyC₁₋₆alkyl, —(CH₂)_(k)—O—C₁₋₆alkyl,—(CH₂)_(k)—O-(hydroxyC₁₋₆alkyl), hydroxyC₁₋₆alkoxy,—(CH₂)_(k)—CO₂C₁₋₆alkyl, —(CH₂)_(k)—CO₂H, —C₁₋₆alkyl-N(H)_(e)(C₁₋₄alkyl)_(2-e), —(CH₂)_(j)—C₃₋₈cycloalkyl and—(CH₂)_(j)—C₃₋₈cycloalkenyl;

R^(x) and R^(y) are independently selected from hydrogen, halogen,nitro, nitrile, C₁₋₆alkyl, haloC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,hydroxy, hydroxyC₁₋₆alkyl, C₁₋₆alkoxy, —(CH₂)_(k)—O—C₁₋₆alkyl,hydroxyC₁₋₆alkoxy, —COOC₁₋₆alkyl, —N(H)_(e)(C₁₋₄alkyl)_(2-e),—C₁₋₆alkyl-N(H)_(e)(C₁₋₄alkyl)_(2-e),—(CH₂)_(k)—C(═O)N(H)_(e)(C₁₋₄alkyl)_(2-e), C₃₋₈cycloalkyl andC₃₋₈cycloalkenyl;

or the R^(x) and R^(y) groups, together with the carbon or nitrogen atomto which they are attached, can join to form a C₃₋₆cycloalkyl orsaturated heterocyclyl group with 3 to 6 ring members which may beoptionally fused to an aromatic heterocyclyl group of 3 to 5 ringmembers or can join to form a ═CH group;

j, d, and e are independently selected from 0, 1 and 2;

k is selected from 1 and 2; and

v is independently selected from 0 and 1.

In one embodiment when t is 1 the group —(CR^(x)R^(y))_(q)—X and therest of the molecule are attached to the same carbon atom in the groupA. In one embodiment when t is 1 the group (CR^(x)R^(y))_(q)—X and therest of the molecule are attached to different carbon atoms in the groupA.

In one embodiment, R³ is hydrogen or -(A)_(t)-(CR^(x)R^(y))_(q)—X;

s is selected from 0 and 1;

t is selected from 0 and 1;

q is selected from 0, 1 and 2;

wherein when R³ is -(A)_(t)-(CR^(x)R^(y))_(q)—X then (i) at least one ofs, t and q is other than 0 and (ii) when t is 0 then s is 1 and q isother than 0;

A is a C₃₋₆cycloalkyl group or a heterocyclic group with 3 to 6 ringmembers, wherein the heterocyclic group comprises one or more (e.g. 1,2, or 3) heteroatoms selected from N, O, S and oxidised forms thereof;

X is selected from hydrogen, halogen, —CN, —OR⁹, —(CH₂)_(v)—CO₂H,—(CH₂)_(v)—CO₂C₁₋₄alkyl, —S(O)_(d)—R^(x), —C(═O)—C₁₋₄alkyl,—S(O)_(d)—N(H)_(e)(C₁₋₄alkyl)_(2-e), —NR^(x)R^(y), —NHSO₂R^(x),—NR^(x)COR^(y), and —C(═O)NR^(x)R^(y);

R⁹ is independently selected from hydrogen and C₁₋₆alkyl;

R^(x) and R^(y) are independently selected from hydrogen and C₁₋₆alkyl;

d and e are independently selected from 0, 1 and 2;

v is independently selected from 0 and 1.

In one embodiment, R³ is hydrogen or -(A)_(t)-(CR^(x)R^(y))_(q)—X;

s is selected from 0 and 1;

t is selected from 0 and 1;

q is selected from 0, 1 and 2;

wherein when R³ is -(A)_(t)-(CR^(x)R^(y))_(q)—X then (i) at least one ofs, t and q is other than 0 and (ii) when t is 0 then s is 1 and q isother than 0;

A is a C₃₋₆cycloalkyl group or a heterocyclic group with 3 to 6 ringmembers, wherein the heterocyclic group comprises one or more (e.g. 1,2, or 3) heteroatoms selected from N, O, S and oxidised forms thereof;

X is selected from hydrogen, halogen, —CN, —OR⁹, —(CH₂)_(v)—CO₂H,—(CH₂)_(v)—CO₂C₁₋₄alkyl, —C(═O)—C₁₋₄alkyl, —NR^(x)R^(y), —NR^(x)COR^(y),and —C(═O)NR^(x)R^(y);

R⁹ is independently selected from hydrogen and C₁₋₆alkyl;

R^(x) and R^(y) are independently selected from hydrogen and C₁₋₆alkyl;

v is independently selected from 0 and 1.

In one embodiment, R³ is hydrogen or -(A)_(t)-(CR^(x)R^(y))_(q)—X;

s is selected from 0 and 1;

t is selected from 0 and 1;

q is selected from 0, 1 and 2;

wherein when R³ is -(A)_(t)-(CR^(x)R^(y))_(q)—X then (i) at least one ofs, t and q is other than 0 and (ii) when t is 0 then s is 1 and q isother than 0;

A is a C₃₋₆cycloalkyl group or a heterocyclic group with 3 to 6 ringmembers, wherein the heterocyclic group comprises one or more (e.g. 1,2, or 3) heteroatoms selected from N, O, S and oxidised forms thereof;

X is selected from hydrogen, halogen, —CN, —OR⁹, —NR^(x)COR^(y), and—C(═O)NR^(x)R^(y);

R⁹ is independently selected from hydrogen and C₁₋₆alkyl;

R^(x) and R^(y) are independently selected from hydrogen and C₁₋₆alkyl;

v is independently selected from 0 and 1.

In one embodiment, R³ is hydrogen or -(A)_(t)-(CR^(x)R^(y))_(q)—X;

s is selected from 0 and 1;

t is selected from 0 and 1;

q is selected from 0, 1 and 2;

wherein when R³ is -(A)_(t)-(CR^(x)R^(y))_(q)—X then (i) at least one ofs, t and q is other than 0 and (ii) when t is 0 then s is 1 and q isother than 0;

A is a C₃₋₆cycloalkyl group or a heterocyclic group with 3 to 6 ringmembers, wherein the heterocyclic group comprises one or more (e.g. 1,2, or 3) heteroatoms selected from N, O, S and oxidised forms thereof;

X is selected from hydrogen, halogen (e.g. fluoro), —OR⁹,—NR^(x)COR^(y); and —C(═O)NR^(x)R^(y);

R⁹ is independently selected from hydrogen and C₁₋₆alkyl;

R^(x) and R^(y) are independently selected from hydrogen and C₁₋₆alkyl;

v is independently selected from 0 and 1.

In one embodiment, R³ is hydrogen and s is 1 i.e. the moiety—(CH₂)_(s)R³ is —CH₃.

In one embodiment, R³ is hydrogen and s is 0 i.e. the moiety—(CH₂)_(s)R³ is —H.

In one embodiment, t is 1 and A is a C₃₋₆cycloalkyl group or aheterocyclic group with 3 to 6 ring members, wherein the heterocyclicgroup comprises one or more (e.g. 1 or 2) heteroatoms selected from N,O, S and oxidised forms thereof.

In one embodiment, t is 1 and A is a C₃₋₆cycloalkyl group. In oneembodiment, A is a C₃₋₅cycloalkyl group. For example, A is selected froma cyclopropyl group, a cyclobutyl group and a cyclopentyl group. In oneembodiment, A is a cyclopropyl group. In one embodiment, A is acyclobutyl group.

In particular, t is 1 and A is cyclopropyl.

In one embodiment, t is 1 and A is a heterocyclic group with 3 to 6 ringmembers, wherein the heterocyclic group comprises one or more (e.g. 1,2, or 3) heteroatoms selected from N, O, S and oxidised forms thereof.

In one embodiment, t is 1 and A is a heterocyclic group with 3 to 5 ringmembers, wherein the heterocyclic group comprises one or more (e.g. 1,2, or 3) heteroatoms selected from N, O, S and oxidised forms thereof.

In one embodiment, t is 1 and A is an unsaturated heterocyclic groupwith 3 to 5 ring members, wherein the heterocyclic group comprises oneor more (e.g. 1, 2, or 3) heteroatoms selected from N, O, S and oxidisedforms thereof, in particular O.

In one embodiment, t is 1 and A is a saturated heterocyclic group with 3to 5 ring members, wherein the heterocyclic group comprises one or more(e.g. 1, 2, or 3) heteroatoms selected from N, O, S and oxidised formsthereof, in particular O.

In one embodiment, t is 1 and A is a heterocyclic group which isselected from morpholinyl, piperidinyl (e.g. piperidin-1-yl,piperidin-2-yl, piperidin-3-yl and piperidin-4-yl), piperidinonyl,pyrrolidinyl (e.g. pyrrolidin-1-yl, pyrrolidin-2-yl andpyrrolidin-3-yl), pyrrolidonyl, azetidinyl, oxetanyl, pyranyl (2H-pyranor 4H-pyran), dihydrothienyl, dihydropyranyl, dihydrofuranyl,dihydrothiazolyl, tetrahydrofuranyl (e.g. tetrahydrofuran-3-yl),tetrahydrothienyl, dioxanyl, oxanyl (e.g. oxan-4-yl), imidazolinyl,imidazolidinonyl, oxazolinyl, thiazolinyl, pyrazolin-2-yl,pyrazolidinyl, piperazinonyl, piperazinyl, and N-alkyl piperazines suchas N-methyl piperazinyl.

In one embodiment, t is 1 and A is a heterocyclic group which isselected from morpholinyl, piperidinyl (e.g. piperidin-1-yl,piperidin-2-yl, piperidin-3-yl and piperidin-4-yl), piperidinonyl,pyrrolidinyl (e.g. pyrrolidin-1-yl, pyrrolidin-2-yl andpyrrolidin-3-yl), pyrrolidonyl, azetidinyl, oxetanyl, pyranyl (2H-pyranor 4H-pyran), dihydropyranyl, dihydrofuranyl, dihydrothiazolyl,tetrahydrofuranyl (e.g. tetrahydrofuran-3-yl), dioxanyl, oxanyl (e.g.oxan-4-yl), imidazolinyl, imidazolidinonyl, oxazolinyl, pyrazolin-2-yl,pyrazolidinyl, piperazinonyl, piperazinyl, and N-alkyl piperazines suchas N-methyl piperazinyl.

In particular, t is 1 and A is a heterocyclic group which is oxetanyl(e.g. oxetan-3-yl).

In particular, t is 1 and A is a heterocyclic group which istetrahydrofuranyl (e.g. tetrahydrofuran-3-yl).

In one embodiment, X is hydrogen, s is 0 and q is 0, and R³ is aheterocyclic group with 3 to 6 ring members, wherein the heterocyclicgroup comprises one or more (e.g. 1, 2, or 3) heteroatoms selected fromN, O, S and oxidised forms thereof. In particular, R³ istetrahydrofuranyl (e.g. tetrahydrofuran-3-yl).

In one embodiment, s is 0 and t is 1 and A is attached directly to theoxygen atom bound to the isoindolinone. In one embodiment s is 1 and thecycloalkyl group is attached via a methylene group (i.e. —CH₂—) to theoxygen atom bound to the isoindolinone.

In one embodiment, A is tetrahydrofuranyl and X is hydrogen.

In one embodiment A is selected from cyclopropyl, oxetanyl andtetrahydrofuranyl.

In one embodiment, q is 0. In one embodiment, q is 1. In one embodiment,q is 2.

In one embodiment, A is oxetanyl and X is fluorine.

When q is not 0, R^(x) and R^(y) are selected from hydrogen, halogen(e.g. fluorine), hydroxy and methyl e.g. hydrogen and methyl, inparticular hydrogen.

In one embodiment, q is 1 and at least one R^(x) and R^(y) is hydrogen.In one embodiment, q is 2 and at least two R^(x) and R^(y) are hydrogene.g. three R^(x) and R^(y) are hydrogen.

In one embodiment, —(CR^(x)R^(y))_(q)— is selected from —CH₂— and—CH₂CH₂—.

In one embodiment, R^(x) and R^(y) together form a saturatedheterocyclyl group with 3 to 6 ring members.

In one embodiment t is 0 and —(CR^(x)R^(y))_(q)— is —CH₂—. In oneembodiment t is 0, s is 0, —(CR^(x)R^(y))_(q)— is —CH₂— and X ishydroxy.

In one embodiment, X is selected from —CN, —OH, —O—C₁₋₄alkyl,—O-hydroxyC₁₋₄alkyl, —S(O)_(d)—C₁₋₄alkyl, —C(═O)—C₁₋₄alkyl,—NR^(x)R^(y), —NR^(x)COR^(y) and —C(═O)NR^(x)R^(y).

In one embodiment, X is selected from —CN, —OH, —O—CH₂CH₂OH,—S(O)_(d)—C₁₋₄alkyl and —C(═O)NR^(x)R^(y) (e.g. —C(═O)NH₂ or—C(═O)NH(CH₃)). In one embodiment X is selected from —CN, —OH, —C(═O)NH₂or —C(═O)NH(CH₃).

In one embodiment, X is selected from hydrogen, halogen, —CN, —OR⁹, and—C(═O)NR^(x)R^(y). In another embodiment, X is selected from hydrogen,halogen, —CN, —OH, —OCH₃, and —C(═O)NH₂. In another embodiment, X isselected from hydrogen, fluorine, —CN, —OH, and —C(═O)NH₂.

In one embodiment, X is selected from hydrogen, fluorine, —CN, —OH and—C(═O)NH₂. In one embodiment, X is selected from hydrogen, —CN, —OH and—C(═O)NH₂. In one embodiment, X is selected from —CN, —OH and —C(═O)NH₂.

In one embodiment X is selected from —OH and —C(═O)NH₂ e.g. —OH.

In one embodiment, X is —C(═O)NR^(x)R^(y) (e.g. —C(═O)NH₂ or—C(═O)NH(CH₃).

In one embodiment, R^(x) and R^(y) are hydrogen, halogen (e.g.fluorine), hydroxy and methyl. In one embodiment, R^(x) and R^(y) arehydrogen and methyl. In one embodiment, R^(x) and R^(y) together form asaturated heterocyclyl group with 3 to 6 ring members.

In one embodiment, A is a C₃₋₆cycloalkyl group (i.e. g is 1, 2 or 3) andt is 1 and s is 0 or 1, and the compound of formula (I) is a compound offormula (If) or a tautomer or a solvate or a pharmaceutically acceptablesalt thereof:

In one embodiment, A is a C₃₋₆cycloalkyl group (i.e. g is 1, 2 or 3) andt is 1 and s is 1, and the compound of formula (I) is a compound offormula (Ig) or a tautomer or a solvate or a pharmaceutically acceptablesalt thereof:

In one embodiment, A is a C₃₋₆cycloalkyl group (i.e. g is 1, 2 or 3) andt is 1 and s is 0, and the compound of formula (I) is a compound offormula (Ig′) or a tautomer or a solvate or a pharmaceuticallyacceptable salt thereof:

In one embodiment, the compound of formula (I) is a compound of formula(Ig′) and g is 2.

In one embodiment, A is a C₃₋₆cycloalkyl group (i.e. g is 1, 2 or 3) andt is 1 and s is 1, and the cycloalkyl group is geminally disubstituted(i.e. the group —(CR^(x)R^(y))_(q)—X and the —CH₂—O-isoindolinone groupare both attached to the same atom of the cycloalkyl group), and thecompound of formula (I) is a compound of formula (Ih) or a tautomer or asolvate or a pharmaceutically acceptable salt thereof:

In one embodiment, A is a cyclopropyl group (i.e. g is 1), t is 1 and sis 1. Therefore the cycloalkyl group is a cyclopropyl group and thecompound of formula (I) is a compound of formula (Ii) or a tautomer or asolvate or a pharmaceutically acceptable salt thereof:

In one embodiment, A is a C₃₋₆cycloalkyl group (i.e. g is 1, 2 or 3), tis 1, s is 1 and X is hydroxy, and the compound of formula (I) is acompound of the formula (Ij) or a tautomer or a solvate or apharmaceutically acceptable salt thereof:

In one embodiment, A is a C₃₋₆cycloalkyl group (i.e. g is 1, 2 or 3), tis 1, s is 1 and X is —C(═O)NH₂ and the compound of formula (I) is acompound of the formula (Ik) or a tautomer or a solvate or apharmaceutically acceptable salt thereof:

In one embodiment, A is a C₃₋₆cycloalkyl group (i.e. g is 1, 2 or 3), tis 1, s is 1 and X is —CN and the compound of formula (I) is a compoundof the formula (Ik′) or a tautomer or a solvate or a pharmaceuticallyacceptable salt thereof:

In another embodiment, A is a C₃₋₆cycloalkyl group (i.e. g is 1, 2 or3), t is 1, s is 1 and R^(x) and R^(y) are hydrogen (including ¹H and²H) and the compound of formula (I) is a compound of formula (IL) or atautomer or a solvate or a pharmaceutically acceptable salt thereof:

In one embodiment, A is a cyclopropyl or cyclobutyl group (i.e. g is 1or 2), t is 1, s is 1 and X is hydroxy and the compound of formula (IL)is a compound of formula (Im) or a tautomer or a solvate or apharmaceutically acceptable salt thereof:

In one embodiment, g is 1 and the compound of formula (Im) is a compoundof the formula (Im′) or a tautomer or a solvate or a pharmaceuticallyacceptable salt thereof:

In one embodiment, A is a C₃-cycloalkyl group (i.e. g is 1), t is 1, sis 1 and X is —C(═O)NH₂ and the compound of formula (I) is a compound offormula (In) or a tautomer or a solvate or a pharmaceutically acceptablesalt thereof:

wherein q is 0 or 1. In one embodiment of the compound (In), q is 0.

In one embodiment, A is a C₃-cycloalkyl group (i.e. g is 1), t is 1, sis 1 and X is —CN and the compound of formula (I) is a compound offormula (In′) or a tautomer or a solvate or a pharmaceuticallyacceptable salt thereof:

wherein q is 0 or 1. In one embodiment of the compound (In), q is 0.

In one embodiment of formula (I) and subformulae thereof, the hydrogensin the —(CR^(x)R^(y))— group of R³ are ²H (i.e. deuterium, D). In oneembodiment, the hydrogens in the group —CH₂—O group are ²H (i.e.deuterium, D). In one embodiment, the hydrogens in the —(CR^(x)R^(y))—and —CH₂—O groups are ²H (i.e. deuterium, D).

In one embodiment q is 0 or 1 and R^(x) and R^(y) are hydrogen ordeuterium.

In one embodiment, A is cyclopropyl (i.e. g is 1), t is 1, s is 1, X ishydroxy and the hydrogens in the —(CR^(x)R^(y))— and —CH₂—O groups are²H (or D), and the compound of formula (I) is a compound of formula (Io)or a tautomer or a solvate or a pharmaceutically acceptable saltthereof:

In one embodiment the compound of formula (I) is a compound of formula(Io′) or (Io″) or a tautomer or a solvate or a pharmaceuticallyacceptable salt thereof:

In one embodiment, R³ is —(CR^(x)R^(y))_(q)—X and s is 1, t is 0 and qis 1 or 2, and the compound of formula (I) is a compound of the formula(Ip):

In one embodiment, R^(x) and R^(y) are H, and the compound of formula(Ip) is a compound of the formula (Ip′) or a tautomer or a solvate or apharmaceutically acceptable salt thereof:

In one embodiment, A is a C₃₋₆cycloalkyl group or saturated heterocyclicgroup with 3 to 6 ring members, wherein t is 1, and s is 1, Y isindependently selected from —CH₂—, O, or SO₂, i is 0 or 1, g is 1, 2, 3or 4 and i+g is 1, 2, 3 or 4 and the compound of formula (I) is acompound of the formula (Iq) or a tautomer or a solvate or apharmaceutically acceptable salt thereof:

In one embodiment the compound of formula (I) is a compound of theformula (Iq′) or a tautomer or a solvate or a pharmaceuticallyacceptable salt thereof:

In one embodiment of the compound of formula (Iq′), q is 1 and R^(x),R^(y) and X are hydrogen.

In one embodiment of the compound of formula (Iq′), q is 1, R^(x) andR^(y) are hydrogen, and X is hydroxy.

In one embodiment of the compound of formula (Iq′), q is 1, R^(x) andR^(y) are hydrogen, and X is fluorine.

In one embodiment of the compound of formula (Iq′), q is 0. In oneembodiment of the compound of formula (Iq′), q is 0 and X is fluorine.

In one embodiment q is 0 and X is fluorine and the compound of formula(Iq′) is a compound of the formula (Iq″) or a tautomer or a solvate or apharmaceutically acceptable salt thereof:

In one embodiment of the compound of (Iq′) or the compound of (Iq″), gis 1, i is 1 and Y is O.

In one embodiment g is 1, i is 1, Y is O, q is 0 and X is F and thecompound of formula (Iq′) is a compound of the formula (Iq′″) or atautomer or a solvate or a pharmaceutically acceptable salt thereof:

In one embodiment, i is 1 and Y is O or SO₂, in particular O. In oneembodiment, the compound of formula (Iq) is a compound of formula (Iq″″)or a tautomer or a solvate or a pharmaceutically acceptable saltthereof:

In one embodiment, s is 0, t is 1, A is tetrahydrofuranyl, q is 0 and Xis hydrogen. In one embodiment, R³ is tetrahydrofuranyl and s is 0.

In one embodiment, —(CH₂)_(s)R³ is selected from the following table(point of attachment to the oxygen represented by dashed bond or bondterminus marked “*”):

In one embodiment, —(CH₂)_(s)R³ is selected from the following table(point of attachment to the oxygen represented by dashed bond or bondterminus marked “*”):

In one embodiment A is cyclopropyl, t is 1, s is 1, R^(x) and R^(y) arehydrogen and X is —OH.

In one embodiment A is cyclopropyl, t is 1, s is 1, R^(x) and R^(y) arehydrogen and X is —CN.

In one embodiment R³ is hydrogen and s is 1. In one embodiment, X ishydrogen and s, t, and q are 0.

R⁴ and a

a is 0, 1, 2 or 3. In other words, the phenyl group of theisoindolin-1-one may have 0, 1, 2 or 3 substituents R⁴.

In one embodiment a is 0 or 1. In another embodiment a is 0. In anotherembodiment a is 1.

When a is 2 or 3 (i.e. the phenyl group of the isoindolin-1-one issubstituted with more than one R⁴) the substituents R⁴ may be the sameor different (i.e. are independently selected from the definitions ofR⁴).

In one embodiment, a is 1 and the substituent R⁴ is at the 4-position ofthe isoindolin-1-one, and the compound of formula (I) is a compound offormula (Ir) or a tautomer or a solvate or a pharmaceutically acceptablesalt thereof:

R⁴ is independently selected from halogen, nitrile, C₁₋₄ alkyl,haloC₁₋₄alkyl, C₁₋₄alkoxy and haloC₁₋₄alkoxy.

In one embodiment, R⁴ is halogen. In one embodiment, R⁴ is fluoro orchloro. In another embodiment, R⁴ is fluoro.

In one embodiment, a is 1, the substituent R⁴ is at the 4-position ofthe isoindolin-1-one, and R⁴ is F and the compound of formula (I) is acompound of formula (Is) or a tautomer or a solvate or apharmaceutically acceptable salt thereof:

In one embodiment, a is 0, and the compound of formula (I) is a compoundof formula (It) or a tautomer or a solvate or a pharmaceuticallyacceptable salt thereof:

In one embodiment, R⁴ is C₁₋₄ alkyl (e.g. —CH₃), or halogen (e.g. F orCl) and a is 1.

In one embodiment, a is 0 and R⁴ is absent (i.e. hydrogen).

In one embodiment a is 0 or 1 and R⁴ is halogen (e.g. fluorine).

R⁵ and m

m is 1 or 2. In other words, the phenyl group may have 1 or 2substituents R⁵.

In one embodiment, m is 1 and the phenyl group has one substituent.

R⁵ may be attached at the ortho (or o-), meta (or m-) or para (or p-)position of the phenyl group, wherein the position is defined relativeto the point of attachment of the phenyl group to the 3-position of theisoindolin-1-one ring.

When m is 2 (i.e. the phenyl group is substituted with more than one R⁵)the substituents R⁵ may be the same or different (i.e. are independentlyselected from the definitions of R⁵).

In one embodiment, m is 1 and the substituent R⁴ is at the p-position ofthe phenyl group, and the compound of formula (I) is a compound offormula (Iu) or a tautomer or a solvate or a pharmaceutically acceptablesalt thereof:

R⁵ is independently selected from halogen, nitrile, C₁₋₄ alkyl,haloC₁₋₄alkyl, C₁₋₄alkoxy and haloC₁₋₄alkoxy.

In one embodiment, R⁵ is halogen, C₁₋₄ alkyl, haloC₁₋₄alkyl orC₁₋₄alkoxy. In another embodiment R⁵ is halogen (e.g. chloro).

In one embodiment, R⁵ is halogen (e.g. Cl or F), C₁₋₄ alkyl (e.g.—CH₂CH₃), nitrile, haloC₁₋₄alkyl (e.g. —CF₃, or —CF₂CH₃), orhaloC₁₋₄alkoxy (e.g. —OCF₃), and m is 1 or 2.

In one embodiment, m is 1 and R⁵ is selected from halogen, nitrile, C₁₋₄alkyl, haloC₁₋₄alkyl, C₁₋₄alkoxy and haloC₁₋₄alkoxy.

In one embodiment, m=1 and R⁵ is —Cl (e.g. p-Cl), —F (e.g. 4-F), —CN(e.g. p-CN), —CF₃ (e.g. p-CF₃), —OCF₃ (e.g. p-OCF₃), CF₂CH₃ (e.g.p-CF₂CH₃) or —CH₂CH₃ (e.g. p-CH₂CH₃), or m=2 and R⁵ is p-F or m-F.

In one embodiment, m=1 and R⁵ is —Cl (e.g. p-Cl)

R⁶ and R⁷

R⁶ and R⁷ are independently selected from hydrogen, C₁₋₆alkyl,haloC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, hydroxy, hydroxyC₁₋₆alkyl,—COOC₁₋₆alkyl, —(CH₂)_(j)—O—C₁₋₆alkyl, —(CH₂)_(j)—O-(hydroxyC₁₋₆alkyl),—C₁₋₆alkyl-NR^(x)R^(y), —(CR^(x)R^(y))_(p)—CONR^(x)R^(y),—(CR^(x)R^(y))_(p)—NR^(x)COR^(y),—(CR^(x)R^(y))_(p)—O—CH₂—CONR^(x)R^(y), heterocyclic group with 3 to 7ring members, —CH₂-heterocyclic group with 3 to 7 ring members,—CH₂—O-heterocyclic group with 3 to 7 ring members, —CH₂—NH-heterocyclicgroup with 3 to 7 ring members, —CH₂—N(C₁₋₆alkyl)-heterocyclic groupwith 3 to 7 ring members, —C(═O)NH-heterocyclic group with 3 to 7 ringmembers, C₃₋₈cycloalkyl, —CH₂—C₃₋₈cycloalkyl, —CH₂—O—C₃₋₈cycloalkyl, andC₃₋₈cycloalkenyl, wherein said cycloalkyl, cycloalkenyl or heterocyclicgroups may be optionally substituted by one or more R^(z) groups, andwherein in each instance the heterocyclic group comprises one or more(e.g. 1, 2, or 3) heteroatoms selected from N, O, S and oxidised formsthereof;

or the R⁶ and R⁷ groups, together with the carbon atom to which they areattached, can join to form a C₃₋₆cycloalkyl or heterocyclyl group with 3to 6 ring members, wherein the heterocyclic group comprises one or more(e.g. 1, 2, or 3) heteroatoms selected from N, O, S and oxidised formsthereof, and wherein said C₃₋₆cycloalkyl and heterocyclyl groups may beoptionally substituted by one or more R^(z) groups;

R^(x) and R^(y) are independently selected from hydrogen, halogen,nitro, nitrile, C₁₋₆alkyl, haloC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,hydroxy, hydroxyC₁₋₆alkyl, C₁₋₆alkoxy, —(CH₂)_(k)—O—C₁₋₆alkyl,hydroxyC₁₋₆alkoxy, —COOC₁₋₆alkyl, —N(H)_(e)(C₁₋₄alkyl)_(2-e),—C₁₋₆alkyl-N(H)_(e)(C₁₋₄alkyl)_(2-e),—(CH₂)_(k)—C(═O)N(H)_(e)(C₁₋₄alkyl)_(2-e), C₃₋₈cycloalkyl andC₃₋₈cycloalkenyl;

or the R^(x) and R^(y) groups, together with the carbon or nitrogen atomto which they are attached, can join to form a C₃₋₆cycloalkyl orsaturated heterocyclyl group with 3 to 6 ring members which may beoptionally fused to an aromatic heterocyclyl group of 3 to 5 ringmembers;

or when on a carbon atom the R^(x) and R^(y) groups can join together toform a ═CH₂ group;

R^(z) is independently selected from halogen, nitro, nitrile, C₁₋₆alkyl,haloC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, ═O, hydroxy, hydroxyC₁₋₆alkyl,C₁₋₆alkoxy, —(CH₂)_(k)—O—C₁₋₆alkyl, hydroxyC₁₋₆alkoxy, —C(═O)C₁₋₆alkyl,—C(═O)C₁₋₆alkyl-OH, —C(═O)C₁₋₆alkyl-N(H)_(e)(C₁₋₄alkyl)_(2-e),—C(═O)N(H)_(e)(C₁₋₄alkyl)_(2-e), —(CH₂)_(r)—CO₂C₁₋₆alkyl,—(CH₂)_(r)—CO₂H, —N(H)_(e)(C₁₋₄alkyl)_(2-e),—C₁₋₆alkyl-N(H)_(e)(C₁₋₄alkyl)_(2-e), heterocyclyl group with 3 to 6ring members, heterocyclyl group with 3 to 6 ring members substituted by—C(═O)C₁₋₄alkyl, heterocyclyl group with 3 to 6 ring members substitutedby —C(═O)OC₁₋₄alkyl, heterocyclyl group with 3 to 6 ring memberssubstituted by —C(═O)N(H)_(e)(C₁₋₄alkyl)_(2-e), —C(═O)heterocyclyl groupwith 3 to 6 ring members, C₃₋₈cycloalkyl and C₃₋₈cycloalkenyl, whereinif R⁷ is pyridine then R^(z) is other then —NH₂;

j, e, r and p are independently selected from 0, 1 and 2; and

k is selected from 1 and 2.

In one embodiment, R⁶ and R⁷ are independently selected from hydrogen,C₁₋₆alkyl, haloC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, hydroxy,hydroxyC₁₋₆alkyl, —COOC₁₋₆alkyl, —(CH₂)_(j)—O—C₁₋₆alkyl,—(CH₂)_(j)—O-(hydroxyC₁₋₆alkyl), —C₁₋₆alkyl-NR^(x)R^(y),—(CR^(x)R^(y))_(p)—CONR^(x)R^(y), —(CR^(x)R^(y))_(p)—NR^(x)COR^(y),—(CR^(x)R^(y))_(p)—O—CH₂—CONR^(x)R^(y), heterocyclic group with 3 to 7ring members, —CH₂-heterocyclic group with 3 to 7 ring members,—CH₂—O-heterocyclic group with 3 to 7 ring members, —CH₂—NH-heterocyclicgroup with 3 to 7 ring members, —CH₂—N(C₁₋₆alkyl)-heterocyclic groupwith 3 to 7 ring members, —C(═O)NH-heterocyclic group with 3 to 7 ringmembers, C₃₋₈cycloalkyl, —CH₂—C₃₋₈cycloalkyl, —CH₂—O—C₃₋₈cycloalkyl, andC₃₋₈cycloalkenyl, wherein said cycloalkyl, cycloalkenyl or heterocyclicgroups may be optionally substituted by one or more R^(z) groups, andwherein in each instance the heterocyclic group comprises one or more(e.g. 1, 2, or 3) heteroatoms selected from N, O, S and oxidised formsthereof;

In one embodiment R⁷ is a cycloalkyl, cycloalkenyl or heterocyclic groupoptionally substituted by one or more R^(z) selected from C₁₋₆alkyl(e.g. methyl), C₁₋₆alkoxy (e.g. methoxy) and —C(═O)C₁₋₆alkyl (e.g.—C(═O)CH₃).

In one embodiment R⁷ is a cycloalkyl or cycloalkenyl group optionallysubstituted by one or more R^(z) groups wherein R^(z) is hydroxy.

R⁶ and R⁷ may be the same or different.

When R⁶ and R⁷ are different, the compound of formula (I) can exist asat least two diastereoisomers:

For the avoidance of doubt, the general formula (I) and all subformulaecover both individual diastereoisomers and mixtures of thediastereoisomers which are related as epimers at the —CR⁶R⁷OH group.

In one embodiment of the compound of formula (I) R⁶ and R⁷ are differentand the compound is diastereoisomer 2A or a tautomer or a solvate or apharmaceutically acceptable salt thereof.

In one embodiment of the compound of formula (I) R⁶ and R⁷ are differentand the compound is diastereoisomer 2B or a tautomer or a solvate or apharmaceutically acceptable salt thereof.

In one embodiment, R⁶ is methyl and the compound of formula (I) is acompound of formula (Iv) or a tautomer or a solvate or apharmaceutically acceptable salt thereof:

In one embodiment, R⁶ is ethyl and the compound of formula (I) is acompound of formula (Iv′) or a tautomer or a solvate or apharmaceutically acceptable salt thereof:

In one embodiment, R⁷ is selected from C₁₋₆alkyl or haloC₁₋₆alkyl. Inone embodiment R⁷ is a C₃₋₆cycloalkyl (e.g. cyclopropyl, cyclobutyl orcyclohexyl) optionally substituted by one or more R^(z) groups (e.g.—OH).

In one embodiment, R⁷ is selected from C₁₋₆alkyl, hydroxyC₁₋₆alkyl,—(CH₂)_(j)—O—C₁₋₆alkyl, —(CH₂)_(j)—O-(hydroxyC₁₋₆alkyl),—C₁₋₆alkyl-NR^(x)R^(y) (e.g. —C₁₋₆alkyl-N(H)_(e)(C₁₋₄alkyl)_(2-e)),—(CR^(x)R^(y))_(p)—NR^(x)COR^(y), heterocyclic group with 3 to 7 ringmembers, —CH₂-heterocyclic group with 3 to 7 ring members,—CH₂—NH-heterocyclic group with 3 to 7 ring members,—CH₂—N(C₁₋₆alkyl)-heterocyclic group with 3 to 7 ring members,—C(═O)NH-heterocyclic group with 3 to 7 ring members, C₃₋₈cycloalkyl,and —CH₂—C₃₋₈cycloalkyl, wherein said cycloalkyl or heterocyclic groupsmay be optionally substituted by one or more R^(z) groups, and whereinin each instance the heterocyclic group comprises one or more (e.g. 1,2, or 3) heteroatoms selected from N, O, S and oxidised forms thereof.

In one embodiment, R⁷ is selected from C₁₋₆alkyl, hydroxyC₁₋₆alkyl,—(CH₂)_(j)—O—C₁₋₆alkyl, —(CH₂)_(j)—O-(hydroxyC₁₋₆alkyl),—C₁₋₆alkyl-N(H)_(e)(C₁₋₄alkyl)_(2-e), heterocyclic group with 3 to 7ring members, —CH₂-heterocyclic group with 3 to 7 ring members,—C(═O)NH-heterocyclic group with 3 to 7 ring members, C₃₋₈cycloalkyl,and —CH₂—C₃₋₈cycloalkyl, wherein said cycloalkyl or heterocyclic groupsmay be optionally substituted by one or more R^(z) groups, and whereinin each instance the heterocyclic group comprises one or more (e.g. 1,2, or 3) heteroatoms selected from N, O, S and oxidised forms thereof.

In one embodiment, R⁷ is selected from heterocyclic group with 3 to 7ring members, —CH₂-heterocyclic group with 3 to 7 ring members,—C(═O)NH-heterocyclic group with 3 to 7 ring members, C₃₋₈cycloalkyl,and —CH₂—C₃₋₈cycloalkyl, wherein said cycloalkyl or heterocyclic groupsmay be optionally substituted by one or more R^(z) groups, and whereinin each instance the heterocyclic group comprises one or more (e.g. 1,2, or 3) heteroatoms selected from N, O, S and oxidised forms thereof.

In one embodiment, R⁷ is selected from heterocyclic group with 3 to 7ring members and —CH₂-heterocyclic group with 3 to 7 ring members,wherein said heterocyclic groups may be optionally substituted by one ormore R^(z) groups, and wherein in each instance the heterocyclic groupcomprises one or more (e.g. 1, or 2) heteroatoms selected from N, O, Sand oxidised forms thereof.

In embodiment, the heterocyclic group is saturated. In one embodiment,R⁷ is saturated heterocyclic group with 3 to 6 ring members or—CH₂-(saturated heterocyclic group with 3 to 6 ring members) such aswherein the heterocyclic group is selected from oxetanyl, oxanyl,piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, imidazolinyl,azetidinyl, thiomorpolinyl, such as oxanyl, piperdinyl or piperazinyl.

In one embodiment, R⁷ is selected from saturated heterocyclic group with3 to 6 ring members and —CH₂-saturated heterocyclic group with 3 to 6ring members, wherein said heterocyclic groups may be optionallysubstituted by one or more R^(z) groups, and wherein in each instancethe heterocyclic group comprises one or more (e.g. 1, 2, or 3)heteroatoms selected from N, O, S. In one embodiment, R⁷ is selectedfrom a nitrogen containing saturated heterocyclic group with 3 to 6 ringmember and —CH₂-(nitrogen containing saturated heterocyclic group with 3to 6 ring members), wherein said heterocyclic groups may be optionallysubstituted by one or more R^(z) groups, and wherein the heterocyclicgroup may optionally contain one or more (e.g. 1, 2, or 3) additionalheteroatoms selected from N, O, S.

In one embodiment, R⁷ is nitrogen containing saturated heterocyclicgroup with 3 to 7 ring members or —CH₂-(nitrogen containing saturatedheterocyclic group with 3 to 7 ring members), wherein said nitrogencontaining saturated heterocyclic groups may be optionally substitutedby one or more R^(z) groups and wherein the nitrogen containingsaturated heterocyclic group may optionally contain one or more (e.g. 1,2, or 3) additional heteroatoms selected from N, O, S. In one embodimentthe nitrogen containing saturated heterocyclic group with 3 to 7 ringmembers (such as 3 to 6 ring members) is selected from piperidinyl,piperazinyl, morpholinyl, pyrrolidinyl, imidazolinyl, azetidinyl,thiomorpolinyl, such as piperdinyl or piperazinyl.

In one embodiment, R⁷ is nitrogen containing aromatic heterocyclic groupwith 3 to 6 ring members or —CH₂-(nitrogen containing aromaticheterocyclic group with 3 to 6 ring members), wherein said heterocyclicgroups may be optionally substituted by one or more R^(z) groups andwherein the heterocyclic group may optionally contain one or more (e.g.1, 2, or 3) additional heteroatoms selected from N, O, S.

In another embodiment, R⁷ is nitrogen containing aromatic heterocyclicgroup with 3 to 6 ring members, wherein said heterocyclic group may beunsubstituted or substituted by one or more R^(z) groups, for exampleselected from halogen (e.g. fluorine), C₁₋₆alkyl (e.g. methyl),C₁₋₆alkoxy (e.g. methoxy), and —C(═O)C₁₋₆alkyl (e.g. —C(═O)CH₃).

In one embodiment, R⁷ is oxygen containing aromatic heterocyclic groupwith 3 to 6 ring members or —CH₂-(oxygen containing aromaticheterocyclic group with 3 to 6 ring members), wherein said heterocyclicgroups may be optionally substituted by one or more R^(z) groups andwherein the heterocyclic group may optionally contain one or more (e.g.1, 2, or 3) additional heteroatoms selected from N, O, S.

In another embodiment, R⁷ is oxygen containing aromatic heterocyclicgroup with 3 to 6 ring members, wherein said heterocyclic group may beunsubstituted or substituted by one or more R^(z) groups, for exampleR^(z) groups selected from halogen (e.g. fluorine), C₁₋₆alkyl (e.g.methyl), C₁₋₆alkoxy (e.g. methoxy), and —C(═O)C₁₋₆alkyl (e.g.—C(═O)CH₃).

In one embodiment R⁷ is selected from heterocyclyl groups containing 5or 6 ring members optionally substituted by one or more R^(z).

In one embodiment R⁷ is selected from aromatic heterocyclyl groupscontaining 5 ring members optionally substituted by one or more R^(z).In one embodiment R⁷ is selected from an aromatic nitrogen containing(e.g. diaza) heteterocyclyl group containing 5 ring members optionallysubstituted by one or more R^(z). In one embodiment R⁷ is pyrazolyl(e.g. pyrazol-4-yl or pyrazol-3-yl).

In one embodiment R⁷ is selected from a saturated heteterocyclyl groupcontaining 6 ring members optionally substituted by one or more R^(z).In one embodiment R⁷ is selected from a saturated oxygen or nitrogencontaining heteterocyclyl group containing 6 ring members optionallysubstituted by one or more R^(z).

In one embodiment R⁷ is selected from oxanyl, piperidinyl, pyrazolyl orimidazolyl optionally substituted by one or more R^(z). In oneembodiment R⁷ is selected from oxanyl, piperidinyl, pyrazolyl orimidazolyl optionally substituted by one or more R^(z), where R^(z) isselected from halo (e.g. —F) or C₁₋₄alkyl (e.g. methyl).

In one embodiment R⁷ is selected from oxanyl (also known astetrahydropyranyl) or piperidinyl optionally substituted by one or moreR^(z). In one embodiment R⁷ is selected from oxanyl or piperidinylunsubstituted or substituted by one or more R^(z), where R^(z) isselected from halo (e.g. —F) or C₁₋₄alkyl (e.g. methyl), in particularhalo (e.g. —F).

In one embodiment, R⁷ is C₃₋₈cycloalkyl such as C₃₋₆cycloalkyl (e.g.cyclobutyl or cyclohexyl) optionally substituted by one or more R^(z),for example where R^(z) is hydroxy. In one embodiment, R⁷ is cyclohexyloptionally substituted by one or more hydroxy. In one embodiment R⁷ iscyclohexyl optionally substituted by one or more hydroxyl, in the transstereochemistry (e.g. trans-4-hydroxycyclohexane).

In one embodiment R⁷ is selected from —CH₂—NH-heterocyclic group with 3to 7 ring members (e.g. —CH₂—NH-oxanyl and—CH₂—N(C₁₋₆alkyl)-heterocyclic group with 3 to 7 ring members (e.g.—CH₂NCH₃-(piperidinyl) optionally substituted by one or more R^(z)groups (e.g. methyl, —COCH₃).

In one embodiment, R⁷ is —(CR^(x)R^(y))_(p)—CONR^(x)R^(y) or—C(═O)NH-heterocyclic group with 3 to 7 ring members. In one embodiment,R⁷ is —C(═O)NH-heterocyclic group with 4 to 6 ring members (e.g.piperidinyl, pyrazolyl, or azetidinyl).

In one embodiment, R⁷ is —(CR^(x)R^(y))_(p)—CONR^(x)R^(y). In oneembodiment R⁷ is —(CR^(x)R^(y))_(p)—CONH(C₁₋₄alkyl), in particular—(CO)NHCH₃, —(CO)NHCH₂CH₃ or —(CO)NH(CH(CH₃)₂).

In one embodiment R⁷ is —C(═O)NH-heterocyclic group with 3 to 7 ringmembers (e.g. —C(═O)NH-piperidinyl, —C(═O)NH-azetidinyl or—C(═O)NH-pyrazolyl) optionally substituted by one or more R^(z) groups(e.g. methyl, —COCH₃).

In one embodiment, R⁷ is —C₁₋₆alkyl-NR^(x)R^(y) (e.g.—C₁₋₆alkyl-N(H)_(e)(C₁₋₄alkyl)_(2-e)). In one embodiment R⁷ is —CH₂NH₂,—CH₂NHCH₃, or —CH₂N(CH₃)₂. In one embodiment R⁷ is—C₁₋₆alkyl-NR^(x)R^(y) wherein R^(x) is C₃₋₈cycloalkyl. In oneembodiment R⁷ is —C₁₋₂alkyl-NH—C₃₋₆cycloalkyl (e.g.—CH₂—NH-cyclopropyl).

In one embodiment, R⁷ is —C₁₋₆alkyl-NR^(x)R^(y) wherein the R^(x) andR^(y) groups, together with the nitrogen atom to which they areattached, can join to form a C₃₋₆cycloalkyl or heterocyclyl group with 3to 6 ring members. In one embodiment, R^(x) and R^(y) together form asaturated heterocyclyl group with 3 to 6 ring members e.g. piperazinyl.

In one embodiment R⁷ is —C₁₋₆alkyl-NR^(x)R^(y), wherein the R^(x) andR^(y) groups, together with the nitrogen atom to which they areattached, join to form a C₃₋₆cycloalkyl or saturated heterocyclyl groupwith 3 to 6 ring members which may be optionally fused to an aromaticheterocyclyl group of 3 to 5 ring members. In one embodiment R⁷ is—C₁₋₆alkyl-NR^(x)R^(y), wherein the R^(x) and R^(y) groups, togetherwith the nitrogen atom to which they are attached, join to form asaturated heterocyclyl group with 3 to 6 ring members which is fused toan aromatic heterocyclyl group of 3 to 5 ring members. R^(z) isindependently selected from halogen, nitro, nitrile, C₁₋₆alkyl,haloC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, ═O, hydroxy, hydroxyC₁₋₆alkyl,C₁₋₆alkoxy, —(CH₂)_(k)—O—C₁₋₆alkyl, hydroxyC₁₋₆alkoxy, —C(═O)C₁₋₆alkyl,—C(═O)C₁₋₆alkyl-OH, —C(═O)C₁₋₆alkyl-N(H)_(e)(C₁₋₄alkyl)_(2-e),—C(═O)N(H)_(e)(C₁₋₄alkyl)_(2-e), —(CH₂)_(r)—CO₂C₁₋₆alkyl,—(CH₂)_(r)—CO₂H, —N(H)_(e)(C₁₋₄alkyl)_(2-e),—C₁₋₆alkyl-N(H)_(e)(C₁₋₄alkyl)_(2-e), heterocyclyl group with 3 to 6ring members, heterocyclyl group with 3 to 6 ring members substituted by—C(═O)C₁₋₄alkyl, heterocyclyl group with 3 to 6 ring members substitutedby —C(═O)OC₁₋₄alkyl, heterocyclyl group with 3 to 6 ring memberssubstituted by —C(═O)N(H)_(e)(C₁₋₄alkyl)_(2-e), —C(═O)heterocyclyl groupwith 3 to 6 ring members, C₃₋₈cycloalkyl and C₃₋₈cycloalkenyl.

In one embodiment R^(z) is independently selected from halogen (e.g.fluorine), C₁₋₆alkyl (e.g. methyl), C₁₋₆alkoxy (e.g. methoxy), and—C(═O)C₁₋₆alkyl (e.g. —C(═O)CH₃).

In one embodiment R^(z) is independently selected from C₁₋₆alkyl (e.g.methyl), C₁₋₆alkoxy (e.g. methoxy), and —C(═O)C₁₋₆alkyl (e.g.—C(═O)CH₃).

In one embodiment, R⁷ is C₁₋₆alkyl (e.g. methyl or ethyl), haloC₁₋₆alkyl(e.g. trifluoromethyl), C₂₋₆alkenyl (e.g. C₂alkenyl), hydroxyC₁₋₆alkyl(e.g. —CH₂OH, —CH₂CH₂OH), —C₁₋₆alkyl-NR^(x)R^(y) (e.g. —CH₂NH₂,—CH₂NHCH₃, —CH₂N(CH₃)₂, or —CH₂—NH-cyclopropyl),—(CR^(x)R^(y))_(p)—CONR^(x)R^(y) (e.g. —(CO)NHCH₃, —(CO)NHCH₂CH₃,—(CO)NHCH₂CH₂NH₂ or —(CO)NH(CH(CH₃)₂), —(CH₂)_(j)—O—C₁₋₆alkyl (e.g.—CH₂OCH₃, —CH₂OCH₂CH₃ or —CH₂OCD₃), —(CR^(x)R^(y))_(p)—NR^(x)COR^(y)(e.g. —CH₂NHCOCH₃), —(CR^(x)R^(y))_(p)—O—CH₂—CONR^(x)R^(y) (e.g.—CH₂—O—CH₂CON(CH₃)₂), —(CH₂)_(j)—O-(hydroxyC₁₋₆alkyl) (e.g.—CH₂—O—CH₂CH₂OH), —C(═O)NH-heterocyclic group with 3 to 7 ring members,C₃₋₆cycloalkyl, heterocyclic group with 3 to 7 ring members (e.g.oxanyl), or —CH₂-heterocyclic group with 3 to 7 ring members wherein thecycloalkyl or heterocyclic group comprises one or more (e.g. 1, 2, or 3)heteroatoms selected from N, O, S and oxidised forms and may beoptionally substituted by one or more R^(z) groups (for example selectedfrom C₁₋₆alkyl (e.g. methyl), C₁₋₆alkoxy (e.g. methoxy) and—C(═O)C₁₋₆alkyl (e.g. —C(═O)CH₃)). In one embodiment, R⁶ is methyl orethyl and R⁷ is C₁₋₆alkyl (e.g. methyl), hydroxyC₁₋₆alkyl,—C₁₋₆alkyl-NR^(x)R^(y), —(CR^(x)R^(y))_(p)—CONR^(x)R^(y),—(CH₂)_(j)—O—C₁₋₆alkyl, —(CR^(x)R^(y))_(p)—NR^(x)COR^(y),—(CR^(x)R^(y))_(p)—O—CH₂—CONR^(x)R^(y), —(CH₂)_(j)—O-(hydroxyC₁₋₆alkyl),heterocyclic group with 3 to 7 ring members (e.g. oxanyl), or—CH₂-heterocyclic group with 3 to 7 ring members wherein theheterocyclic group comprises one or more (e.g. 1, 2, or 3) heteroatomsselected from N, O, S and oxidised forms and may be optionallysubstituted by one or more R^(z) groups selected from C₁₋₆alkyl (e.g.methyl), C₁₋₆alkoxy (e.g. methoxy) and —C(═O)C₁₋₆alkyl (e.g. —C(═O)CH₃).

In one embodiment, R⁶ is selected from hydrogen, C₁₋₆alkyl (e.g. —CH₃,—CH₂CH₃ or —CH₂CH₂CH₃), C₂₋₆alkenyl (e.g. —CH═CH₂) and haloC₁₋₆alkyl(e.g. —CF₃).

In one embodiment, R⁶ is selected from hydrogen or C₁₋₆alkyl (e.g. —CH₃or —CH₂CH₃).

In one embodiment, R⁷ is C₁₋₆alkyl (e.g. —CH₃ or —CH₂CH₃),hydroxyC₁₋₆alkyl (e.g. —CH₂OH), —C₁₋₆alkyl-NR^(x)R^(y) (e.g.—CH₂N(CH₃)₂), —(CR^(x)R^(y))_(p)—CONR^(x)R^(y) (e.g. —C(═O)N(CH₃)₂ or—C(═O)NHCH₃ or

—(CH₂)_(j)—O—C₁₋₆alkyl (e.g. —CH₂OCH₃), C₃₋₈cycloalkyl (e.g. cyclobutylor cyclohexyl), heterocyclic group with 3 to 7 ring members e.g.

(point of attachment represented by dashed bond):

or —CH₂-heterocyclic group with 3 to 7 ring members e.g.

(point of attachment represented by dashed bond)

wherein when the moiety R⁷ comprises a heterocyclic or cycloalkyl group,the heterocyclic group may be optionally substituted by one or moreR^(z) groups selected from C₁₋₆alkyl (e.g. methyl), hydroxy, halogen(e.g. fluoro), —C(═O)C₁₋₆alkyl (e.g. —C(═O)C(CH₃)₃), —(CH₂)_(r)—CO₂H(e.g. —CH₂COOH or CH₂CH₂COOH or —(CH₂)_(r)—CO₂C₁₋₆alkyl (e.g.CH₂CH₂COOCH₃).

In one embodiment, R⁷ is C₁₋₆alkyl (e.g. methyl or ethyl), haloC₁₋₆alkyl(e.g. trifluoromethyl), C₂₋₆alkenyl (e.g. C₂alkenyl), hydroxyC₁₋₆alkyl(e.g. —CH₂OH, —CH₂CH₂OH), —C₁₋₆alkyl-NR^(x)R^(y) (e.g. —CH₂NH₂,—CH₂NHCH₃, —CH₂N(CH₃)₂, or —CH₂—NH-cyclopropyl),—(CR^(x)R^(y))_(p)—CONR^(x)R^(y) (e.g. —(CO)NHCH₃, —(CO)NHCH₂CH₃,—(CO)NHCH₂CH₂NH₂ or —(CO)NH(CH(CH₃)₂), —(CH₂)_(j)—O—C₁₋₆alkyl (e.g.—CH₂OCH₃, —CH₂OCH₂CH₃ or —CH₂OCD₃), —(CR^(x)R^(y))_(p)—NR^(x)COR^(y)(e.g. —CH₂NHCOCH₃), —(CR^(x)R^(y))_(p)—O—CH₂—CONR^(x)R^(y) (e.g.—CH₂—O—CH₂CON(CH₃)₂), —(CH₂)_(j)—O-(hydroxyC₁₋₆alkyl) (e.g.—CH₂—O—CH₂CH₂OH), —C(═O)NH-heterocyclic group with 3 to 7 ring members,C₃₋₆cycloalkyl, heterocyclic group with 3 to 7 ring members (e.g.oxanyl), or —CH₂-heterocyclic group with 3 to 7 ring members wherein thecycloalkyl or heterocyclic group comprises one or more (e.g. 1, 2, or 3)heteroatoms selected from N, O, S and oxidised forms and may beoptionally substituted by one or more R^(z) groups (for example selectedfrom C₁₋₆alkyl (e.g. methyl), C₁₋₆alkoxy (e.g. methoxy) and—C(═O)C₁₋₆alkyl (e.g. —C(═O)CH₃)). In one embodiment, R⁶ is methyl orethyl and R⁷ is C₁₋₆alkyl (e.g. methyl), hydroxyC₁₋₆alkyl,—C₁₋₆alkyl-NR^(x)R^(y), —(CR^(x)R^(y))_(p)—CONR^(x)R^(y),—(CH₂)_(j)—O—C₁₋₆alkyl, —(CR^(x)R^(y))_(p)—NR^(x)COR^(y),—(CR^(x)R^(y))_(p)—O—CH₂—CONR^(x)R^(y), —(CH₂)_(j)—O-(hydroxyC₁₋₆alkyl),heterocyclic group with 3 to 7 ring members (e.g. oxanyl), or—CH₂-heterocyclic group with 3 to 7 ring members wherein theheterocyclic group comprises one or more (e.g. 1, 2, or 3) heteroatomsselected from N, O, S and oxidised forms and may be optionallysubstituted by one or more R^(z) groups selected from C₁₋₆alkyl (e.g.methyl), C₁₋₆alkoxy (e.g. methoxy) and —C(═O)C₁₋₆alkyl (e.g. —C(═O)CH₃).

In one embodiment, R⁶ is selected from hydrogen or C₁₋₆alkyl (e.g. —CH₃or —CH₂CH₃).

In one embodiment, R⁷ is C₁₋₆alkyl (e.g. —CH₃ or —CH₂CH₃),hydroxyC₁₋₆alkyl (e.g. —CH₂OH o), —C₁₋₆alkyl-NR^(x)R^(y) (e.g.—CH₂N(CH₃)₂), —(CR^(x)R^(y))_(p)—CONR^(x)R^(y) (e.g. —C(═O)N(CH₃)₂ or

(CH₂)_(j)—O—C₁₋₆alkyl (e.g. —CH₂OCH₃), heterocyclic group with 3 to 7ring members e.g.

(point of attachment represented by dashed bond):

or —CH₂-heterocyclic group with 3 to 7 ring members e.g.

(point of attachment represented by dashed bond)

wherein when the moiety R⁷ comprises a heterocyclic group, theheterocyclic group may be optionally substituted by one or more R^(z)groups selected from C₁₋₆alkyl (e.g. methyl).

In one embodiment of formula (I) R⁷ is a heterocyclic group with 3 to 7ring members optionally substituted by one or more R^(z) groups e.g.

(point of attachment represented by dashed bond)

In one embodiment of formula (I) R⁷ is a heterocyclic group with 3 to 7ring members optionally substituted by one or more R^(z) groups e.g.

(point of attachment represented by dashed bond)

In one embodiment, R⁷ is a —CH₂-heterocyclic group with 3 to 7 ringmembers optionally substituted by by one or more R^(z) groups e.g.

(point of attachment represented by dashed bond)

In one embodiment, R⁷ is selected from:

(point of attachment represented by dashed bond):

In one embodiment, R⁷ is selected from:

(point of attachment represented by dashed bond):

In one embodiment, R⁶ is hydrogen or C₁₋₆alkyl. In one embodiment, R⁶ isC₁₋₆alkyl. In one embodiment, R⁶ is methyl or ethyl. In one embodiment,R⁶ is ethyl.

In one embodiment, R⁶ is C₁₋₆alkyl (such as methyl or ethyl e.g. methyl)and R⁷ is selected from hydroxyC₁₋₆alkyl and —(CH₂)—O—C₁₋₆alkyl, In oneembodiment, R⁶ is methyl and R⁷ is selected from methyl, —CH₂—OH and—CH₂—OCH₃. In one embodiment R⁶ is methyl and R⁷ is methyl, ethyl, orpropyl.

In one embodiment R⁶ is methyl and R⁷ is methyl.

In one embodiment, R⁶ is C₁₋₆alkyl or haloC₁₋₆alkyl (e.g. methyl,-monofluoromethyl, trifluoromethyl or ethyl).

In one embodiment, R⁶ is C₃₋₈cycloalkyl such as C₃₋₆cycloalkyl (e.g.cyclopropyl).

In one embodiment R⁶ is C₁₋₆alkyl (such as methyl or ethyl e.g. ethyl)and R⁷ is selected from: (point of attachment represented by dashed bondor bond terminus marked “*”):

In one embodiment R⁶ is C₁₋₆alkyl (such as methyl or ethyl e.g. ethyl)and R⁷ is selected from: (point of attachment represented by dashed bondor bond terminus marked “*”):

In particular, R⁷ is:

(point of attachment represented by dashed bond):

In one embodiment, R⁶ is C₁₋₆alkyl (such as methyl or ethyl e.g. methyl)and R⁷ is oxanyl, and the compound of formula (I) is a compound offormula (Iw):

In one embodiment of formula (Iw) R_(z) is hydrogen or fluorine.

In one embodiment, R⁷ is imidazolyl and the compound of formula (I) is acompound of formula (Ix) or a tautomer or a solvate or apharmaceutically acceptable salt thereof:

In one embodiment, R⁷ is N-methyl piperidinyl and the compound offormula (I) is a compound of formula (Ix′) or a tautomer or a solvate ora pharmaceutically acceptable salt thereof:

In one embodiment, R⁷ is 4-fluoro-1-methylpiperidin-4-yl and thecompound of formula (I) is a compound of formula (Ix″) or a tautomer ora solvate or a pharmaceutically acceptable salt thereof:

In one embodiment, R⁷ is pyrazolyl optionally substituted by one or moreR^(z) groups (e.g. methyl). In one embodiment, R⁷ isN-methylpyrazol-3-yl or N-methylpyrazol-4-yl.

In one embodiment, R⁷ is selected from methyl, oxanyl, pyrazolyl,imidazolyl, piperidinyl, and cyclohexyl wherein said cycloalkyl andheterocyclic groups are optionally substituted by one or more R^(z)groups (e.g. methyl, fluorine, or hydroxyl).

In one embodiment, R⁷ is selected from piperidinyl optionallysubstituted by one or more R^(z) groups (e.g. methyl, fluorine, orhydroxyl, in particular methyl and fluorine).

In one embodiment, the compound of formula (I) is a compound of formula(Ix) and R⁶ is C₁₋₄alkyl.

In one embodiment, R⁶ is C₁₋₆alkyl (e.g. —CH₃, —CH₂CH₃ or —CH₂CH₂CH₃such as methyl or ethyl e.g. ethyl) and R⁷ is a heterocyclic group with3 to 7 ring members optionally substituted by one or more R^(z) groups.

In one embodiment, R⁶ is C₁₋₆alkyl (e.g. —CH₃, —CH₂CH₃ or —CH₂CH₂CH₃such as methyl or ethyl e.g. ethyl) and R⁷ is imidazolyl optionallysubstituted by one or more R^(z) groups (e.g. methyl imidazolyl).

In one embodiment, R⁶ is C₁₋₆alkyl (e.g. —CH₃, —CH₂CH₃ or —CH₂CH₂CH₃such as methyl or ethyl e.g. ethyl) and R⁷ is piperidinyl optionallysubstituted by one or more R^(z) groups (e.g. methyl piperidinyl).

In one embodiment R⁶ is C₁₋₆alkyl (e.g. —CH₃, —CH₂CH₃ or —CH₂CH₂CH₃ suchas methyl or ethyl e.g. ethyl) and R⁷ is C₁₋₄alkyl, hydroxylC₁₋₄alkyl,methoxyC₁₋₄alkyl, a heterocyclic group with 5 or 6 ring members orC₃₋₆cycloalkyl, wherein the heterocyclic group or C₃₋₆cycloalkyl groupis optionally substituted by one or more R^(z) (e.g. methyl, halogen(such as fluorine), C(═O)Me, or —OH).

In one embodiment R⁶ is C₁₋₆alkyl (e.g. —CH₃, —CH₂CH₃ or —CH₂CH₂CH₃ suchas methyl or ethyl e.g. ethyl) and R⁷ is methyl, ethyl, hydroxylmethyl,hydroxyethyl, methoxymethyl, piperidinyl, oxanyl, imidazolyl, pyrazolyl,cyclobutyl, cyclohexyl, optionally substituted by one or more R^(z)(e.g. methyl, halogen (such as fluorine), C(═O)Me, or —OH).

In one embodiment, R⁶ and R⁷ are both the same. In one embodiment, R⁶and R⁷ are both methyl, and the compound of formula (I) is a compound offormula (Iy) or a tautomer or a solvate or a pharmaceutically acceptablesalt thereof:

In one embodiment the group —CR⁶R⁷OH is other than —C(CH₃)₂OH.

In one embodiment, R⁷ is selected from the group consisting of:

(point of attachment represented by dashed bond)

In one embodiment, R⁷ is selected from the group consisting of:

(point of attachment represented by dashed bond)

In one embodiment R^(z) is independently selected from halogen, nitro,nitrile, C₁₋₆alkyl, haloC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, ═O,hydroxy, hydroxyC₁₋₆alkyl, C₁₋₆alkoxy, —(CH₂)_(k)—O—C₁₋₆alkyl,hydroxyC₁₋₆alkoxy, —C(═O)C₁₋₆alkyl, —C(═O)C₁₋₆alkyl-OH,—C(═O)C₁₋₆alkyl-N(H)_(e)(C₁₋₄alkyl)_(2-e),—C(═O)N(H)_(e)(C₁₋₄alkyl)_(2-e), —(CH₂)_(k)—CO₂C₁₋₆alkyl,—(CH₂)_(r)—CO₂H, —NH(C₁₋₄alkyl), —N(C₁₋₄alkyl)₂,—C₁₋₆alkyl-N(H)_(e)(C₁₋₄alkyl)_(2-e), heterocyclyl group with 3 to 6ring members, heterocyclyl group with 3 to 6 ring members substituted by—C(═O)C₁₋₄alkyl, heterocyclyl group with 3 to 6 ring members substitutedby —C(═O)OC₁₋₄alkyl, heterocyclyl group with 3 to 6 ring memberssubstituted by —C(═O)N(H)_(e)(C₁₋₄alkyl)_(2-e), —C(═O)heterocyclyl groupwith 3 to 6 ring members, C₃₋₈cycloalkyl and C₃₋₈cycloalkenyl.

In another embodiment R^(z) is independently selected from halogen,nitro, nitrile, C₁₋₆alkyl, haloC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, ═O,hydroxy, hydroxyC₁₋₆alkyl, C₁₋₆alkoxy, —(CH₂)_(k)—O—C₁₋₆alkyl,hydroxyC₁₋₆alkoxy, —C(═O)C₁₋₆alkyl, —C(═O)C₁₋₆alkyl-OH,—C(═O)C₁₋₆alkyl-N(H)_(e)(C₁₋₄alkyl)_(2-e),—C(═O)N(H)_(e)(C₁₋₄alkyl)_(2-e), —(CH₂)_(r)—CO₂C₁₋₆alkyl,—(CH₂)_(r)—CO₂H, —C₁₋₆alkyl-N(H)_(e)(C₁₋₄alkyl)_(2-e), heterocyclylgroup with 3 to 6 ring members, heterocyclyl group with 3 to 6 ringmembers substituted by —C(═O)C₁₋₄alkyl, heterocyclyl group with 3 to 6ring members substituted by —C(═O)OC₁₋₄alkyl, heterocyclyl group with 3to 6 ring members substituted by —C(═O)N(H)_(e)(C₁₋₄alkyl)_(2-e),—C(═O)heterocyclyl group with 3 to 6 ring members, C₃₋₈cycloalkyl andC₃₋₈cycloalkenyl.

In another embodiment when R⁷ contains a saturated heterocyclic groupthen R^(z) is independently selected from halogen, nitro, nitrile,C₁₋₆alkyl, haloC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, ═O, hydroxy,hydroxyC₁₋₆alkyl, C₁₋₆alkoxy, —(CH₂)_(k)—O—C₁₋₆alkyl, hydroxyC₁₋₆alkoxy,—C(═O)C₁₋₆alkyl, —C(═O)C₁₋₆alkyl-OH,—C(═O)C₁₋₆alkyl-N(H)_(e)(C₁₋₄alkyl)_(2-e),—C(═O)N(H)_(e)(C₁₋₄alkyl)_(2-e), —(CH₂)_(r)—CO₂C₁₋₆alkyl,—(CH₂)_(r)—CO₂H, —N(H)_(e)(C₁₋₄alkyl)_(2-e),—C₁₋₆alkyl-N(H)_(e)(C₁₋₄alkyl)_(2-e), heterocyclyl group with 3 to 6ring members, heterocyclyl group with 3 to 6 ring members substituted by—C(═O)C₁₋₄alkyl, heterocyclyl group with 3 to 6 ring members substitutedby —C(═O)OC₁₋₄alkyl, heterocyclyl group with 3 to 6 ring memberssubstituted by —C(═O)N(H)_(e)(C₁₋₄alkyl)_(2-e), —C(═O)heterocyclyl groupwith 3 to 6 ring members, C₃₋₈cycloalkyl and C₃₋₈cycloalkenyl.

Subformulae

In one embodiment, the compound of formulae (I) is a compound offormulae (II) or a tautomer or a solvate or a pharmaceuticallyacceptable salt thereof:

wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, a, m and s are as defined herein.

In one embodiment, R¹ is chloro, nitrile, methyl or methoxy. In oneembodiment, R¹ is hydroxy or hydroxyC₁₋₄alkyl (e.g. hydroxyl).

In one embodiment, R¹ is O_(0,1)(CR^(x)R^(y))_(v)COOH (e.g. —COOH,—CH₂COOH, —OCH₂COOH or —C(CH₃)₂COOH.

In another embodiment, R¹ is chloro or nitrile and the compound offormula (II) is a compound of formula (IIa) or (IIb) or a tautomer or asolvate or a pharmaceutically acceptable salt thereof:

wherein R², R³, R⁴, R⁵, R⁷, m and s are as defined herein. In oneembodiment, R¹ is —SO₂₋R^(x). In particular, R^(x) is —SO₂—C₁₋₄alkyl,for example —SO₂—CH₃ or —SO₂-heterocyclic group with 5 to 6 ring members(e.g. —SO₂-morpholinyl, typically —SO₂-(1-morpholinyl). In anotherembodiment In one embodiment, R¹ is hydroxy or hydroxyC₁₋₄alkyl (e.g.—CH₂OH or —OH).

In one embodiment, R⁶ is methyl or ethyl, and the compound of formula(I) is a compound of formula (IIIa) or (IIIb) or a tautomer or a solvateor a pharmaceutically acceptable salt thereof:

wherein R¹, R², R³, R⁴, R⁵, R⁷, a, m and s are as defined herein.

In one embodiment, a is 1 and the compound of formula (I) is a compoundof formula (IVa) or a tautomer or a solvate or a pharmaceuticallyacceptable salt thereof:

wherein R¹, R², R³, R⁴, R⁵, R⁷, a, m and s are as defined herein.

In one embodiment, s is 0 and the compound of formula (I) is a compoundof formula (IVb) or a tautomer or a solvate or a pharmaceuticallyacceptable salt thereof:

wherein R¹, R², R³, R⁴, R⁵, R⁷, a, m and s are as defined herein.

In one embodiment, R⁴ is F and the compound of formula (IVa) is acompound of formula (V) or a tautomer or a solvate or a pharmaceuticallyacceptable salt thereof:

wherein R¹, R², R³, R⁵, R⁷, m and s are as defined herein.

In one embodiment, m is 1 and the substituent R⁴ is at the 4-position ofthe phenyl group, and the compound of formula (I) is a compound offormula (VI) or a tautomer or a solvate or a pharmaceutically acceptablesalt thereof:

In one embodiment, R⁵ is chloro and the compound of formula (VI) is acompound of formula (VIa) or a tautomer or a solvate or apharmaceutically acceptable salt thereof:

In one embodiment, A is a C₃₋₆cycloalkyl group (g is 1, 2 or 3) and t is1, and the compound of formula (VI) is a compound of formula (VII) or atautomer or a solvate or a pharmaceutically acceptable salt thereof:

In one embodiment, A is a C₃₋₆cycloalkyl group (g is 1, 2 or 3) and t is1, and the cycloalkyl group is geminally disubstituted (i.e. the group—(CR^(x)R^(y))—X and the CH₂ group (where s is 1) or the oxygen atom(where s is 0) are both attached to the same atom of the cycloalkylgroup, and the compound of formula (VII) is a compound of formula (VIIa)or a tautomer or a solvate or a pharmaceutically acceptable saltthereof:

In one embodiment, g is 1, and so the cycloalkyl group is a cyclopropylgroup and the compound of formula (VIIa) is a compound of formula (VIIb)or a tautomer or a solvate or a pharmaceutically acceptable saltthereof:

In one embodiment, s is 1, and the compound of formula (VIIb) is acompound of formula (VIIc) or a tautomer or a solvate or apharmaceutically acceptable salt thereof:

In one embodiment, R^(x) and R^(y) are hydrogen (including ¹H and ²H)and q is 1 and the compound of formula (VIIc) is a compound of (VIId) ora tautomer or a solvate or a pharmaceutically acceptable salt thereof:

In one embodiment, the compound of formula (VIId) is a compound of(VIId′) or a tautomer or a solvate or a pharmaceutically acceptable saltthereof:

In one embodiment, the compound of formula (VIId) is a compound of(VIId′) and X is hydroxy.

In one embodiment, X is hydroxy, and the compound of formula (VIId) is acompound of the formula (VIIe) or a tautomer or a solvate or apharmaceutically acceptable salt thereof:

In one embodiment, X is —C(═O)NH₂ and the compound of formula (VIIe) isa compound of the formula (VIIe′) or a tautomer or a solvate or apharmaceutically acceptable salt thereof:

wherein q is 0 or 1, and in particular q is 0.

In one embodiment, X is —CN and the compound of formula (VIId) is acompound of the formula (VIIe″) or a tautomer or a solvate or apharmaceutically acceptable salt thereof:

wherein q is 0 or 1, and in particular q is 0.

In one embodiment, R³ is methyl, and the compound of formula (VI) is acompound of formula (VIIf) or a tautomer or a solvate or apharmaceutically acceptable salt thereof:

In one embodiment of Formula (VIIa-e′) R⁶ is methyl. In one embodimentof Formula (VIIa-e′) R⁶ is ethyl.

In one embodiment of Formula (VIIe″) or (VIIf) R⁶ is methyl. In oneembodiment of Formula (VIIe″) or (VIIf) R⁶ is ethyl.

In one embodiment of Formula (VIIe″) or (VIIf) R⁶ is methyl. In oneembodiment of Formula (VIIe″) or (VIIf) R⁶ is ethyl.

In one embodiment of the compound of formula (VIIa-e′), R⁷ is selectedfrom methyl, oxanyl, pyrazolyl, imidazolyl, piperidinyl, and cyclohexylwherein said cycloalkyl and heterocyclic groups are optionallysubstituted by one or more R^(z) groups (e.g. methyl, fluorine, orhydroxy).

In one embodiment of the compound of formula (VIIa-e′), R⁷ is selectedfrom oxanyl and methyl.

In one embodiment of the compound of formula (VIIe″) or (VIIf), R⁷ isselected from methyl, oxanyl, pyrazolyl, imidazolyl, piperidinyl, andcyclohexyl wherein said cycloalkyl and heterocyclic groups areoptionally substituted by one or more R^(z) groups (e.g. methyl,fluorine, or hydroxy).

In one embodiment of the compound of formula (VIIe″) or (VIIf), R⁷ isselected from oxanyl and methyl.

In one embodiment of the compound of formula (VIIa-f), R⁷ is selectedfrom piperidinyl optionally substituted by one or more R^(z) groups(e.g. methyl, fluorine, or hydroxy).

In another embodiment, the compound of formula (I) is a compound offormula (a) or a tautomer or a solvate or a pharmaceutically acceptablesalt thereof:

wherein R¹ is chloro or nitrile, when s is 1 then X is hydroxyl or whens is 0 then X is —C(═O)NH₂.

In another embodiment, the compound of formula (I) is a compound offormula (a′) or a tautomer or a solvate or a pharmaceutically acceptablesalt thereof:

wherein R¹ is chloro or nitrile, when s is 1 then X is hydroxyl or whens is 0 then X is —CN.

In another embodiment, the compound of formula (I) is a compound offormula (a″) or a tautomer or a solvate or a pharmaceutically acceptablesalt thereof:

wherein R¹ is chloro or nitrile, when s is 1 then X is hydroxyl or whens is 0 then X is —C(═O)NH₂.

In another embodiment, the compound of formula (I) is a compound offormula (a′) or a tautomer or a solvate or a pharmaceutically acceptablesalt thereof:

wherein R¹ is chloro or nitrile, when s is 1 then X is hydroxyl or whens is 0 then X is —CN.

In one embodiment of the compound of formula (a), R⁷ is selected frommethyl, oxanyl, pyrazolyl, imidazolyl, piperidinyl, and cyclohexylwherein said cycloalkyl and heterocyclic groups are optionallysubstituted by one or more R^(z) groups (e.g. methyl, fluorine, orhydroxy).

In one embodiment of the compound of formula (a), R⁷ is oxanyl ormethyl.

In one embodiment of the compound of formula (a), R⁷ is piperidinyl,optionally substituted with C₁₋₆ alkyl (e.g. methyl) and/or halo (e.g.flouro).

In one embodiment of the compound of formula (a′), (a″) or (a′″) R⁷ isselected from methyl, oxanyl, pyrazolyl, imidazolyl, piperidinyl, andcyclohexyl wherein said cycloalkyl and heterocyclic groups areoptionally substituted by one or more R^(z) groups (e.g. methyl,fluorine, or hydroxy).

In one embodiment of the compound of formula (a′), (a″) or (a′″) R⁷ isoxanyl or methyl.

In one embodiment of the compound of formula (a′), (a″) or (a′″) R⁷ ispiperidinyl, optionally substituted with C₁₋₆ alkyl (e.g. methyl) and/orhalo (e.g. flouro).

In one embodiment, A is a heterocyclyl group with 3 to 6 ring members,wherein the heterocyclic group comprises one or more (e.g. 1, 2, or 3)heteroatoms selected from N, O, S and oxidised forms thereof (t is 1; gis 1, 2, 3 or 4; Z represents N, O, S and oxidised forms thereof; i is1, 2, or 3; and i+g=2, 3, 4 or 5), and the compound of formula (VI) is acompound of formula (b) or a tautomer or a solvate or a pharmaceuticallyacceptable salt thereof:

In one embodiment, Y is O and i is 1 and the compound of formula (b) isa compound of formula (ba) or a tautomer or a solvate or apharmaceutically acceptable salt thereof:

In one embodiment, s is 0, g is 2, q is 0 and X is hydrogen, and thecompound of formula (b) is a compound of formula (bb) or a tautomer or asolvate or a pharmaceutically acceptable salt thereof:

In one embodiment, s is 0, g is 1, Y is O and i is 1 and the compound offormula (b) is a compound of formula (bc) or a tautomer or a solvate ora pharmaceutically acceptable salt thereof:

In one embodiment, the compound of formula (bc) is where q is 0 and X isfluorine.

In another embodiment, the compound of formula (I) is a compound offormula (c) or a tautomer or a solvate or a pharmaceutically acceptablesalt thereof:

wherein R¹ is chloro or nitrile, s is 1 and X is hydroxyl or s is 0 andX is —C(═O)NH₂.

In another embodiment, the compound of formula (I) is a compound offormula (c′) or a tautomer or a solvate or a pharmaceutically acceptablesalt thereof:

wherein R¹ is chloro or nitrile, s is 1 and X is hydroxyl or s is 0 andX is —CN.

In another embodiment, the compound of formula (I) is a compound offormula (c″) or a tautomer or a solvate or a pharmaceutically acceptablesalt thereof:

wherein R¹ is chloro or nitrile, s is 1 and X is hydroxyl or s is 0 andX is —C(═O)NH₂.

In another embodiment, the compound of formula (I) is a compound offormula (c′″) or a tautomer or a solvate or a pharmaceuticallyacceptable salt thereof:

wherein R¹ is chloro or nitrile, s is 1 and X is hydroxyl or s is 0 andX is —CN.

In one embodiment of the compound of formula (c), R⁷ is selected frommethyl, oxanyl, pyrazolyl, imidazolyl, piperidinyl, and cyclohexylwherein said cycloalkyl and heterocyclic groups are optionallysubstituted by one or more R^(z) groups (e.g. methyl, fluorine, orhydroxy).

In one embodiment of the compound of formula (c), R⁷ is oxanyl ormethyl.

In one embodiment of the compound of formula (c), R⁷ is piperidinyl,optionally substituted with C₁₋₆ alkyl (e.g. methyl) and/or halo (e.g.flouro).

In one embodiment of the compound of formula (c′), (c″) or (c′″) R⁷ isselected from methyl, oxanyl, pyrazolyl, imidazolyl, piperidinyl, andcyclohexyl wherein said cycloalkyl and heterocyclic groups areoptionally substituted by one or more R^(z) groups (e.g. methyl,fluorine, or hydroxy).

In one embodiment of the compound of formula (c′), (c″) or (c′″) R⁷ isoxanyl or methyl.

In one embodiment of the compound of formula (c′), (c″) or (c′″) R⁷ ispiperidinyl, optionally substituted with C₁₋₆ alkyl (e.g. methyl) and/orhalo (e.g. flouro).

In another embodiment of the subsformulae described hereinabove, R² isselected from hydrogen and —(R^(x)R^(y))_(u)—CO₂H (e.g. —COOH, —CH₂COOH,—CH₂CH₂—CO₂H, —(CH(CH₃))—CO₂H and —(C(CH₃)₂—CO₂H).

In another embodiment of the subsformulae described hereinabove, R² isselected from —(CH(CH₃))—CO₂H and —(C(CH₃)₂—CO₂H).

In another embodiment, R² is selected from —(CH(CH₃))—CO₂H and—(C(CH₃)₂—CO₂H)

or —(C(CH₃)₂—CO₂H.

In one embodiment, the invention provides a compound of formula (I) or atautomer or a solvate or a pharmaceutically acceptable salt thereofwherein:

R¹ is independently selected from hydroxy, halogen, nitro, nitrile,C₁₋₄alkyl, haloC₁₋₄alkyl, hydroxyC₁₋₄alkyl, C₂₋₆alkenyl, C₁₋₄alkoxy,haloC₁₋₄alkoxy, and C₂₋₄alkynyl;

R² is selected from hydrogen, C₁₋₄ alkyl, C₂₋₆alkenyl, hydroxyC₁₋₄alkyland —CH₂CO₂H;

R³ is hydrogen or -(A)_(t)-(CR^(x)R^(y))_(q)—X;

s and t are independently selected from 0 and 1;

q is selected from 0, 1 and 2;

wherein when R³ is -(A)_(t)-(CR^(x)R^(y))_(q)—X then (i) at least one ofs, t and q is other than 0 and (ii) when t is 0 then s is 1 and q isother than 0;

A is a C₃₋₆cycloalkyl group or a heterocyclic group with 3 to 6 ringmembers, wherein the heterocyclic group comprises one or more (e.g. 1,2, or 3) heteroatoms selected from N, O, S and oxidised forms thereof;

X is selected from hydrogen, halogen, —CN, —OR⁹, —(CH₂)_(v)—CO₂H,—(CH₂)_(v)—CO₂C₁₋₄alkyl, —C(═O)—C₁₋₄alkyl, —NR^(x)R^(y), —NHSO₂R^(x),—NR^(x)COR^(y); and —C(═O)NR^(x)R^(y);

R⁴ and R⁵ are independently selected from halogen, nitrile, C₁₋₄ alkyl,haloC₁₋₄alkyl, C₁₋₄alkoxy and haloC₁₋₄alkoxy;

R⁶ and R⁷ are independently selected from hydrogen, C₁₋₆alkyl,haloC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, hydroxy, hydroxyC₁₋₆alkyl,—COOC₁₋₆alkyl, heterocyclic group with 3 to 7 ring members,—CH₂-heterocyclic group with 3 to 7 ring members, —CH₂—O-heterocyclicgroup with 3 to 7 ring members, —CH₂—NH-heterocyclic group with 3 to 7ring members, —CH₂—N(C₁₋₆alkyl)-heterocyclic group with 3 to 7 ringmembers, —C(═O)NH-heterocyclic group with 3 to 7 ring members,C₃₋₈cycloalkyl, —CH₂—C₃₋₈cycloalkyl, —CH₂—O—C₃₋₈cycloalkyl, andC₃₋₈cycloalkenyl, wherein said cycloalkyl, cycloalkenyl or heterocyclicgroups may be optionally substituted by one or more R^(z) groups, andwherein in each instance the heterocyclic group comprises one or more(e.g. 1, 2, or 3) heteroatoms selected from N, O, S and oxidised formsthereof;

R⁹ is selected from hydrogen, C₁₋₆alkyl, haloC₁₋₆alkyl,hydroxyC₁₋₆alkyl, —(CH₂)_(k)—O—C₁₋₆alkyl,—(CH₂)_(k)—O-(hydroxyC₁₋₆alkyl), hydroxyC₁₋₆alkoxy,—(CH₂)_(k)—CO₂C₁₋₆alkyl, —(CH₂)_(k)—CO₂H,—C₁₋₆alkyl-N(H)_(e)(C₁₋₄alkyl)_(2-e), —(CH₂)_(j)—C₃₋₈cycloalkyl and—(CH₂)_(j)—C₃₋₈cycloalkenyl;

R^(x) and R^(y) are independently selected from hydrogen, halogen,nitro, nitrile, C₁₋₆alkyl, haloC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,hydroxy, hydroxyC₁₋₆alkyl, C₁₋₆alkoxy, —(CH₂)_(k)—O—C₁₋₆alkyl,hydroxyC₁₋₆alkoxy, —COOC₁₋₆alkyl, —N(H)_(e)(C₁₋₄alkyl)_(2-e),—C₁₋₆alkyl-N(H)_(e)(C₁₋₄alkyl)_(2-e),—(CH₂)_(k)—C(═O)N(H)_(e)(C₁₋₄alkyl)_(2-e) C₃₋₈cycloalkyl andC₃₋₈cycloalkenyl;

R^(z) is independently selected from halogen, nitro, nitrile, C₁₋₆alkyl,haloC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, ═O, hydroxy, hydroxyC₁₋₆alkyl,C₁₋₆alkoxy, —(CH₂)_(k)—O—C₁₋₆alkyl, hydroxyC₁₋₆alkoxy, —C(═O)C₁₋₆alkyl,—C(═O)C₁₋₆alkyl-OH, —C(═O)C₁₋₆alkyl-N(H)_(e)(C₁₋₄alkyl)_(2-e),—C(═O)N(H)_(e)(C₁₋₄alkyl)_(2-e), —(CH₂)_(r)—CO₂C₁₋₆alkyl,—(CH₂)_(r)—CO₂H, —N(H)_(e)(C₁₋₄alkyl)_(2-e),—C₁₋₆alkyl-N(H)_(e)(C₁₋₄alkyl)_(2-e), heterocyclyl group with 3 to 6ring members, heterocyclyl group with 3 to 6 ring members substituted by—C(═O)C₁₋₄alkyl, heterocyclyl group with 3 to 6 ring members substitutedby —C(═O)OC₁₋₄alkyl, heterocyclyl group with 3 to 6 ring memberssubstituted by —C(═O)N(H)_(e)(C₁₋₄alkyl)_(2-e), —C(═O)heterocyclyl groupwith 3 to 6 ring members, C₃₋₈cycloalkyl and C₃₋₈cycloalkenyl;

n, e, r and j are independently selected from 0, 1 and 2;

k and m are independently selected from 1 and 2; and

v and a are independently selected from 0 and 1.

In one embodiment, the invention provides a compound of formula (I) or atautomer or a solvate or a pharmaceutically acceptable salt thereof,wherein:

R¹ is independently selected from hydroxy, halogen, nitro, nitrile andC₁₋₄alkyl;

R² is selected from hydrogen, C₁₋₄ alkyl, C₂₋₆alkenyl, hydroxyC₁₋₄alkyland —CH₂CO₂H;

R³ is hydrogen or -(A)_(t)-(CR^(x)R^(y))_(q)—X;

s and t are independently selected from 0 and 1;

q is selected from 0, 1 and 2;

wherein when R³ is -(A)_(t)-(CR^(x)R^(y))_(q)—X then (i) at least one ofs, t and q is other than 0 and (ii) when t is 0 then s is 1 and q isother than 0;

A is a C₃₋₆cycloalkyl group or a heterocyclic group with 3 to 6 ringmembers, wherein the heterocyclic group comprises one or more (e.g. 1,2, or 3) heteroatoms selected from N, O, S and oxidised forms thereof;

X is selected from hydrogen, halogen, —CN, —OR⁹, —(CH₂)_(v)—CO₂H,—(CH₂)_(v)—CO₂C₁₋₄alkyl, —C(═O)—C₁₋₄alkyl, —NR^(x)R^(y), —NHSO₂R^(x),—NR^(x)COR^(y); and —C(═O)NR^(x)R^(y);

R⁴ and R⁵ are independently selected from halogen, nitrile and C₁₋₄alkyl;

R⁶ is selected from hydrogen, C₁₋₆alkyl, haloC₁₋₆alkyl, C₂₋₆alkenyl, andC₂₋₆alkynyl;

R⁷ is selected from hydrogen, C₁₋₆alkyl, haloC₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, hydroxy, hydroxyC₁₋₆alkyl, —COOC₁₋₆alkyl, heterocyclicgroup with 3 to 7 ring members, —CH₂-heterocyclic group with 3 to 7 ringmembers, —CH₂—O-heterocyclic group with 3 to 7 ring members,—CH₂—NH-heterocyclic group with 3 to 7 ring members,—CH₂—N(C₁₋₆alkyl)-heterocyclic group with 3 to 7 ring members,—C(═O)NH-heterocyclic group with 3 to 7 ring members, C₃₋₈cycloalkyl,—CH₂—C₃₋₈cycloalkyl, —CH₂—O—C₃₋₈cycloalkyl, and C₃₋₈cycloalkenyl,wherein said cycloalkyl, cycloalkenyl or heterocyclic groups may beoptionally substituted by one or more R^(z) groups, and wherein in eachinstance the heterocyclic group comprises one or more (e.g. 1, 2, or 3)heteroatoms selected from N, O, S and oxidised forms thereof;

R⁹ is selected from hydrogen, C₁₋₆alkyl, haloC₁₋₆alkyl,hydroxyC₁₋₆alkyl, —(CH₂)_(k)—O—C₁₋₆alkyl,—(CH₂)_(k)—O-(hydroxyC₁₋₆alkyl), hydroxyC₁₋₆alkoxy,—(CH₂)_(k)—CO₂C₁₋₆alkyl, —(CH₂)_(k)—CO₂H, —C₁₋₆alkyl-N(H)_(e)(C₁₋₄alkyl)_(2-e), —(CH₂)_(j)—C₃₋₈cycloalkyl and—(CH₂)_(j)—C₃₋₈cycloalkenyl;

R^(x) and R^(y) are independently selected from hydrogen, halogen,nitro, nitrile, C₁₋₆alkyl, haloC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,hydroxy, hydroxyC₁₋₆alkyl, C₁₋₆alkoxy, —(CH₂)_(k)—O—C₁₋₆alkyl,hydroxyC₁₋₆alkoxy, —COOC₁₋₆alkyl, —N(H)_(e)(C₁₋₄alkyl)_(2-e),—C₁₋₆alkyl-N(H)_(e)(C₁₋₄alkyl)_(2-e),—(CH₂)_(k)—C(═O)N(H)_(e)(C₁₋₄alkyl)_(2-e), C₃₋₈cycloalkyl andC₃₋₈cycloalkenyl;

R^(z) is independently selected from halogen, nitro, nitrile, C₁₋₆alkyl,haloC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, ═O, hydroxy, hydroxyC₁₋₆alkyl,C₁₋₆alkoxy, —(CH₂)_(k)—O—C₁₋₆alkyl, hydroxyC₁₋₆alkoxy, —C(═O)C₁₋₆alkyl,—C(═O)C₁₋₆alkyl-OH, —C(═O)C₁₋₆alkyl-N(H)_(e)(C₁₋₄alkyl)_(2-e),—C(═O)N(H)_(e)(C₁₋₄alkyl)_(2-e), —(CH₂)_(r)—CO₂C₁₋₆alkyl,—(CH₂)_(r)—CO₂H, —N(H)_(e)(C₁₋₄alkyl)_(2-e),—C₁₋₆alkyl-N(H)_(e)(C₁₋₄alkyl)_(2-e), heterocyclyl group with 3 to 6ring members, heterocyclyl group with 3 to 6 ring members substituted by—C(═O)C₁₋₄alkyl, heterocyclyl group with 3 to 6 ring members substitutedby —C(═O)OC₁₋₄alkyl, heterocyclyl group with 3 to 6 ring memberssubstituted by —C(═O)N(H)_(e)(C₁₋₄alkyl)_(2-e), —C(═O)heterocyclyl groupwith 3 to 6 ring members, C₃₋₈cycloalkyl and C₃₋₈cycloalkenyl;

n, e, r and j are independently selected from 0, 1 and 2;

k and m are independently selected from 1 and 2; and

v and a are independently selected from 0 and 1.

In one embodiment, the invention provides a compound of formula (I) or atautomer or a solvate or a pharmaceutically acceptable salt thereof,wherein:

R¹ is independently selected from hydroxy, halogen, nitro, nitrile andC₁₋₄alkyl;

R² is selected from hydrogen, C₁₋₄ alkyl, C₂₋₆alkenyl, hydroxyC₁₋₄alkyland —CH₂CO₂H;

R³ is hydrogen or -(A)_(t)-(CR^(x)R^(y))_(q)—X;

s and t are independently selected from 0 and 1;

q is selected from 0, 1 and 2;

wherein when R³ is -(A)_(t)-(CR^(x)R^(y))_(q)—X then (i) at least one ofs, t and q is other than 0 and (ii) when t is 0 then s is 1 and q isother than 0;

A is a heterocyclic group with 3 to 6 ring members, wherein theheterocyclic group comprises one or more (e.g. 1, 2, or 3) heteroatomsselected from N, O, S and oxidised forms thereof;

X is selected from hydrogen, halogen, —CN and —OR⁹;

R⁴ and R⁵ are independently selected from halogen, nitrile and C₁₋₄alkyl;

R⁶ is selected from hydrogen and C₁₋₆alkyl;

R⁷ is selected from heterocyclic group with 3 to 7 ring members,—CH₂-heterocyclic group with 3 to 7 ring members, C₃₋₈cycloalkyl, and—CH₂—C₃₋₈cycloalkyl, wherein said cycloalkyl or heterocyclic groups maybe optionally substituted by one or more R^(z) groups, and wherein ineach instance the heterocyclic group comprises one or more (e.g. 1, 2,or 3) heteroatoms selected from N, O, S and oxidised forms thereof;

R⁹ is selected from hydrogen and C₁₋₆alkyl;

R^(x) and R^(y) are independently selected from hydrogen and C₁₋₆alkyl;

R^(z) is independently selected from halogen, nitro, nitrile, C₁₋₆alkyl,haloC₁₋₆alkyl, C₂₋₆alkenyl, hydroxy, hydroxyC₁₋₆alkyl, C₁₋₆alkoxy,—C(═O)C₁₋₆alkyl, and —N(H)_(e)(C₁₋₄alkyl)_(2-e);

n and e are independently selected from 0, 1 and 2

m is selected from 1 and 2; and

a is selected from 0 and 1.

In one embodiment, the invention provides a compound of formula (I) or atautomer or a solvate or a pharmaceutically acceptable salt thereof,wherein:

R¹ is independently selected from halogen, hydroxy and nitrile;

R² is selected from hydrogen, C₁₋₄ alkyl and —CH₂CO₂H;

R³ is -(A)_(t)-(CR^(x)R^(y))_(q)—X;

A is a heterocyclic group with 3 to 6 ring members, wherein theheterocyclic group comprises one or more (e.g. 1, 2, or 3) heteroatomsselected from N, O, S and oxidised forms thereof;

s and t are independently selected from 0 and 1;

q is selected from 0, 1 and 2;

wherein (i) at least one of s, t and q is other than 0 and (ii) when tis 0 then s is 1 and q is other than 0;

X is selected from hydrogen, halogen or —OR⁹;

R⁴ and R⁵ are independently selected from halogen;

R⁶ is selected from hydrogen and C₁₋₆alkyl;

R⁷ is selected from heterocyclic group with 3 to 7 ring members,—CH₂-heterocyclic group with 3 to 7 ring members, C₃₋₈cycloalkyl, and—CH₂—C₃₋₈cycloalkyl, wherein said cycloalkyl, cycloalkenyl orheterocyclic groups may be optionally substituted by one or more R^(z)groups, and wherein in each instance the heterocyclic group comprisesone or more (e.g. 1, 2, or 3) heteroatoms selected from N, O, S andoxidised forms thereof;

R⁹ is selected from hydrogen and C₁₋₆alkyl;

R^(x) and R^(y) are independently selected from hydrogen and C₁₋₆alkyl;

R^(z) is independently selected from halogen, nitro, nitrile, andC₁₋₆alkyl;

n is 1 and m is 1; and

a is selected from 0 and 1.

In one embodiment, the invention provides a compound of formula (I) or atautomer or a solvate or a pharmaceutically acceptable salt thereof,wherein:

R¹ is independently selected from halogen, hydroxy and nitrile;

R² is selected from hydrogen, C₁₋₄ alkyl and —CH₂CO₂H;

R³ is -(A)_(t)-(CR^(x)R^(y))_(q)—X;

A is a heterocyclic group with 3 to 6 ring members, wherein theheterocyclic group comprises one or more (e.g. 1, 2, or 3) heteroatomsselected from N, O, S and oxidised forms thereof;

s and t are independently selected from 0 and 1;

q is selected from 0, 1 and 2;

wherein (i) at least one of s, t and q is other than 0 and (ii) when tis 0 then s is 1 and q is other than 0;

X is selected from hydrogen, halogen and —OR⁹;

R⁴ and R⁵ are independently selected from halogen;

R⁶ is selected from hydrogen and C₁₋₆alkyl;

R⁷ is a heterocyclic group with 3 to 7 ring members optionallysubstituted by one or more R^(z) groups;

R⁹ is selected from hydrogen and C₁₋₆alkyl;

R^(x) and R^(y) are independently selected from hydrogen and C₁₋₆alkyl;

R^(z) is independently selected from halogen and C₁₋₆alkyl; and

n is, 1 and m is 1; and

a is 1.

In one embodiment, the invention provides a compound of formula (I) or atautomer or a solvate or a pharmaceutically acceptable salt thereof,wherein:

R¹ is halogen (e.g. Cl), C₁₋₄alkynyl (e.g. —C≡CH), nitrile,hydroxyC₁₋₄alkyl (e.g. CH₂OH), —O_(0,1)(CR^(x)R^(y))_(v)COOH (e.g.—COOH, —CH₂COOH, —OCH₂COOH or —C(CH₃)₂COOH, —S(O)_(d)—C₁₋₄alkyl (e.g.SCH₃, SOCH₃, or SO₂CH₃), —SO₂-(1-morpholinyl) or —P(═O)(R^(x))₂, (e.g.—P(═O)(CH₃)₂);

n is 1 or 2;

R² is hydrogen, C₁₋₄ alkyl (e.g. —CH₃), hydroxyC₁₋₄alkyl (e.g. CH₂OH) or—(CH₂)_(u)COOH (e.g. —CH₂COOH, —CH₂CH₂—CO₂H or —(CH(CH₃))—CO₂H);

the moiety —(CH₂)_(s)R³ is selected from:

(point of attachment to the oxygen represented by dashed bond or bondterminus indicated by *):

R⁴ is halogen (e.g. F);

a is 0 or 1;

R⁵ is halogen (e.g. Cl);

m is 1;

R⁶ is hydrogen or C₁₋₆alkyl (e.g. —CH₃ or —CH₂CH₃);

R⁷ is C₁₋₆alkyl (e.g. —CH₃ or —CH₂CH₃), hydroxyC₁₋₆alkyl (e.g. —CH₂OH),—C₁₋₆alkyl-NR^(x)R^(y) (e.g. —CH₂N(CH₃)₂),—(CR^(x)R^(y))_(p)—CONR^(x)R^(y) (e.g. —C(═O)N(CH₃)₂ or —C(═O)NHCH₃ or

—(CH₂)_(j)—O—C₁₋₆alkyl (e.g. —CH₂OCH₃), C₃₋₈cycloalkyl (e.g. cyclobutylor cyclohexyl), heterocyclic group with 3 to 7 ring members e.g.

(point of attachment represented by dashed bond)

or —CH₂-heterocyclic group with 3 to 7 ring members e.g.

(point of attachment represented by dashed bond)

wherein when the moiety R⁷ comprises a heterocyclic or cycloalkyl group,the heterocyclic group may be optionally substituted by one or moreR^(z) groups selected from C₁₋₆alkyl (e.g. methyl), hydroxy, halogen(e.g. fluoro), —C(═O)C₁₋₆alkyl (e.g. —C(═O)C(CH₃)₃), —(CH₂)_(r)—CO₂H(e.g. —CH₂COOH or CH₂CH₂COOH or —(CH₂)_(r)—CO₂C₁₋₆alkyl (e.g.CH₂CH₂COOCH₃).

In one embodiment, the invention provides a compound of formula (I) or atautomer or a solvate or a pharmaceutically acceptable salt thereof,wherein:

R¹ is halogen (e.g. Cl), C₁₋₄alkynyl (e.g. —C≡CH), nitrile,hydroxyC₁₋₄alkyl (e.g. CH₂OH), —(CH₂)_(v)COOH (e.g. —COOH),—S(O)_(d)—C₁₋₄alkyl (e.g. SCH₃, SOCH₃, or SO₂CH₃), —SO₂-(1-morpholinyl)or —P(═O)(R^(x))₂, (e.g. —P(═O)(CH₃)₂);

n is 1 or 2;

R² is hydrogen, C₁₋₄ alkyl (e.g. —CH₃), hydroxyC₁₋₄alkyl (e.g. CH₂OH) or—(CH₂)_(u)COOH (e.g. —CH₂COOH);

the moiety —(CH₂)_(s)R³ is selected from:

(point of attachment to the oxygen represented by dashed bond or bondterminus indicated by *):

R⁴ is halogen (e.g. F);

a is 0 or 1;

R⁵ is halogen (e.g. Cl);

m is 1;

R⁶ is hydrogen or C₁₋₆alkyl (e.g. —CH₃ or —CH₂CH₃);

R⁷ is C₁₋₆alkyl (e.g. —CH₃), hydroxyC₁₋₆alkyl (e.g. —CH₂OH),—(CH₂)_(j)—O—C₁₋₆alkyl (e.g. —CH₂OCH₃), —C₁₋₆alkyl-NR^(x)R^(y) (e.g.—CH₂N(CH₃)₂), —(CR^(x)R^(y))_(p)—CONR^(x)R^(y) (e.g. —C(═O)N(CH₃)₂ or—C(═O)NHCH₃) or

heterocyclic group with 3 to 7 ring members e.g.

(point of attachment represented by dashed bond)

or —CH₂-heterocyclic group with 3 to 7 ring members e.g.

(point of attachment represented by dashed bond)

wherein when R⁷ comprises a heterocyclic group, the heterocyclic groupmay be optionally substituted by one or more R^(z) groups selected fromC₁₋₆alkyl (e.g. methyl).

In one embodiment of formula (I) R⁷ is a heterocyclic group with 3 to 7ring members e.g.

(point of attachment represented by dashed bond)

In one embodiment of formula wherein when R⁷ comprises a heterocyclicgroup, the heterocyclic group may be R⁷ is a heterocyclic group with 3to 7 ring members optionally substituted by one or more R^(z) groupse.g.

(point of attachment represented by dashed bond)

or a —CH₂-heterocyclic group with 3 to 7 ring members optionallysubstituted by one or more R^(z) groups e.g.

(point of attachment represented by dashed bond)

In one embodiment of formula wherein when R⁷ comprises a heterocyclicgroup, the heterocyclic group may be R⁷ is a heterocyclic group with 3to 7 ring members optionally substituted by one or more R^(z) groupse.g.

(point of attachment represented by dashed bond)

or a —CH₂-heterocyclic group with 3 to 7 ring members optionallysubstituted by one or more R^(z) groups e.g.

(point of attachment represented by dashed bond)

In one embodiment, the invention provides a compound of formula (I) or atautomer or a solvate or a pharmaceutically acceptable salt thereof,wherein:

R¹ is —Cl, —CN, —OH or —OCH₃;

n is 1;

R² is hydrogen;

R³ is hydrogen or -(A)_(t)-(CR^(x)R^(y))_(q)—X;

s is 0 or 1, and t is 1;

A is selected from cyclopropyl, oxetanyl and tetrahydrofuranyl;

X is selected from hydrogen, fluorine, —CN, —OH and —C(═O)NH₂;

q is 0 or 1 and R^(x) and R^(y) are hydrogen or deuterium;

a is 0 or 1 and R⁴ is halogen (e.g. fluorine);

R⁵ is halogen (e.g. Cl);

m is 1;

R⁶ is C₁₋₄alkyl (e.g. methyl or ethyl);

R⁷ is C₁₋₄alkyl (e.g. methyl or ethyl), hydroxylC₁₋₄alkyl (e.g.hydroxylmethyl or hydroxyethyl), methoxyC₁₋₄alkyl (e.g. methoxymethyl),a heterocyclic group with 5 or 6 ring members (e.g. piperidinyl, oxanyl,imidazolyl or pyrazolyl) or C₃₋₆cycloalkyl (e.g. cyclobutyl orcyclohexyl) wherein said heterocyclic group with 5 or 6 ring members andC₃₋₆cycloalkyl groups may be optionally substituted with one or twoR^(z) groups independently selected from methyl, halogen (such asfluorine), —C(═O)Me, and —OH.

In one embodiment, the invention provides a compound of formula (I) or atautomer or a solvate or a pharmaceutically acceptable salt thereof,wherein:

R¹ is —Cl, —CN, —OH or —OCH₃;

n is 1;

R² is hydrogen or —(CH₂)_(u)—CO₂H wherein u is independently selectedfrom 0 and 1; R³ is hydrogen and s is 1 or R³ is-(A)_(t)-(CR^(x)R^(y))_(q)—X and t is 1 and q is 1;

A is selected from cyclopropyl;

X is —OH;

R^(x) and R^(y) are hydrogen or deuterium;

a is 0 or 1 and R⁴ is halogen (e.g. fluorine);

R⁵ is halogen (e.g. Cl);

m is 1;

R⁶ is C₁₋₄alkyl (e.g. methyl or ethyl);

R⁷ is C₁₋₄alkyl (e.g. methyl or ethyl), hydroxylC₁₋₄alkyl (e.g.hydroxylmethyl or hydroxyethyl), methoxyC₁₋₄alkyl (e.g. methoxymethyl),a heterocyclic group with 5 or 6 ring members (e.g. piperidinyl, oxanyl,imidazolyl or pyrazolyl) or C₃₋₆cycloalkyl (e.g. cyclobutyl orcyclohexyl); wherein said heterocyclic group with 5 or 6 ring membersand C₃₋₆cycloalkyl groups may be optionally substituted with one or twoR^(z) groups independently selected from methyl, halogen (such asfluorine), —C(═O)Me, and —OH.

In one embodiment, the invention provides a compound of formula (I) or atautomer or a solvate or a pharmaceutically acceptable salt thereof,wherein:

R¹ is halogen (e.g. Cl) or nitrile;

n is 1;

R² is hydrogen or —(CH₂)_(u)COOH (e.g. —CH₂COOH);

R³ is hydrogen and s is 1 or R³ is -(A)_(t)-(CR^(x)R^(y))_(q)—X and t is1 and q is 1;

A is selected from cyclopropyl;

X is —OH;

R^(x) and R^(y) are hydrogen or deuterium (e.g. hydrogen);

R⁴ is halogen (e.g. F);

a is 0 or 1;

R⁵ is halogen (e.g. Cl);

m is 1;

R⁶ is hydrogen or C₁₋₆alkyl (e.g. —CH₃ or —CH₂CH₃);

R⁷ is C₁₋₄alkyl (e.g. methyl), hydroxylC₁₋₄alkyl (e.g. hydroxylmethyl),methoxyC₁₋₄alkyl (e.g. methoxymethyl), a heterocyclic group with 5 or 6ring members (e.g. piperidinyl, oxanyl, imidazolyl or pyrazolyl));

wherein said heterocyclic group with 5 or 6 ring members may beoptionally substituted with one or two R^(z) groups independentlyselected from C₁₋₄alkyl (e.g. methyl).

In one embodiment, the invention provides a compound of formula (I) or atautomer or a solvate or a pharmaceutically acceptable salt thereof,wherein: R¹ is halogen (e.g. Cl), nitrile, O_(0,1)(CR^(x)R^(y))_(v)COOH(e.g. —COOH, —CH₂COOH, —OCH₂COOH or —C(CH₃)₂COOH;

n is 1 or 2;

R² is selected from hydrogen and —(R^(x)R^(y))_(u)—CO₂H (e.g. —COOH,—CH₂COOH, —CH₂CH₂—CO₂H, —(CH(CH₃))—CO₂H and —(C(CH₃)₂—CO₂H).

R³ is hydrogen and s is 1;

R⁴ is halogen (e.g. F);

R⁵ is halogen (e.g. Cl);

m is 1;

R⁶ is hydrogen or C₁₋₆alkyl (e.g. —CH₃ or —CH₂CH₃);

R⁷ is C₁₋₄alkyl (e.g. methyl), hydroxylC₁₋₄alkyl (e.g. hydroxylmethyl),methoxyC₁₋₄alkyl (e.g. methoxymethyl), a heterocyclic group with 5 or 6ring members (e.g. piperidinyl, oxanyl, imidazolyl or pyrazolyl));

wherein said heterocyclic group with 5 or 6 ring members may beoptionally substituted with one or two R^(z) groups independentlyselected from C₁₋₄alkyl (e.g. methyl).

In one embodiment, the invention provides a compound of formula (I)which is one of the Examples 1-137 or is selected from the Examples1-137 or a tautomer, N-oxide, pharmaceutically acceptable salt orsolvate thereof.

In one embodiment, the invention provides a compound of formula (I)which is one of the Examples 1-97 or is selected from the Examples 1-97or a tautomer, N-oxide, pharmaceutically acceptable salt or solvatethereof.

In one embodiment, the invention provides a compound of formula (I)which is selected from the following compounds, or a tautomer, N-oxide,pharmaceutically acceptable salt or solvate thereof:

-   4-{[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[1-hydroxy-1-(1-methyl-1H-imidazol-4-yl)propyl]-1-{[1-(hydroxymethyl)cyclopropyl]methoxy}-3-oxo-2,3-dihydro-1H-isoindol-2-yl]methyl}benzonitrile;    and-   (3S)-3-(4-chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[1-hydroxy-1-(oxan-4-yl)ethyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]propanoic    acid.

In one embodiment, the invention provides a compound of formula (I)which is diastereoisomer 2A and is selected from the followingcompounds, or a tautomer, N-oxide, pharmaceutically acceptable salt orsolvate thereof:

-   4-{[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[1-hydroxy-1-(1-methyl-1H-imidazol-4-yl)propyl]-1-{[1-(hydroxymethyl)cyclopropyl]methoxy}-3-oxo-2,3-dihydro-1H-isoindol-2-yl]methyl}benzonitrile;    and-   (3S)-3-(4-chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[1-hydroxy-1-(oxan-4-yl)ethyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]propanoic    acid.

In one embodiment, the invention provides a compound of formula (I)which is diastereoisomer 2B and is selected from the followingcompounds, or a tautomer, N-oxide, pharmaceutically acceptable salt orsolvate thereof:

-   4-{[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[1-hydroxy-1-(1-methyl-1H-imidazol-4-yl)propyl]-1-{[1-(hydroxymethyl)cyclopropyl]methoxy}-3-oxo-2,3-dihydro-1H-isoindol-2-yl]methyl}benzonitrile;    and-   (3S)-3-(4-chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[1-hydroxy-1-(oxan-4-yl)ethyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]propanoic    acid.

In one embodiment, the invention provides a compound of formula (I)which is2-(5-chloro-2-{[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[(1S)-1-hydroxy-1-(oxan-4-yl)propyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]methyl}phenyl)-2-methylpropanoicacid, or a tautomer, N-oxide, pharmaceutically acceptable salt orsolvate thereof.

In one embodiment, the invention provides a compound of formula (I)which is(2S,3S)-3-(4-chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[(1S)-1-hydroxy-1-(oxan-4-yl)propyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]-2-methylpropanoicacid, or a tautomer, N-oxide, pharmaceutically acceptable salt orsolvate thereof.

For the avoidance of doubt, it is to be understood that each general andspecific embodiment and example for one substituent may be combined witheach general and specific embodiment and example for one or more, inparticular all, other substituents as defined herein and that all suchembodiments are embraced by this application.

Salts, Solvates, Tautomers, Isomers, N-Oxides, Esters, Prodrugs andIsotopes

A reference to a compound of the formula (I), sub-groups thereof (e.g.formulae I(c), I(f), I(g), I(g′), I(h), I(i), I(j), I(k), I(L), I(m),I(m′), I(n), I(o), I(o′), I(o″), I(p), I(p′), I(q), I(q′), I(q″),I(q′″), I(q″″), I(r), I(s), I(t), I(u), I(v), I(v′), I(w), I(x), I(x′),I(y), (II), (IIa), (IIb), (IIIa), (IIIb), (IVa), (IVb), (V), (VI),(Via), (VII), (VIIa), (VIIb), (VIIc), (VIId), (VIId′), (VIIe), (VIIe′),(a), (b), (ba), (bb), (bc) or (c)) and any example also includes ionicforms, salts, solvates, isomers (including geometric and stereochemicalisomers unless specified), tautomers, N-oxides, esters, prodrugs,isotopes and protected forms thereof, for example, as discussed below;in particular, the salts or tautomers or isomers or N-oxides or solvatesthereof; and more particularly the salts or tautomers or N-oxides orsolvates thereof. In one embodiment reference to a compound of theformula (I), sub-groups thereof (e.g. formulae I(c), I(f), I(g), I(g′),I(h), I(i), I(j), I(k), I(L), I(m), I(m′), I(n), I(o), I(o′), I(o″),I(p), I(p′), I(q), I(q′), I(q″), I(q′″), I(q″″), I(r), I(s), I(t), I(u),I(v), I(v′), I(w), I(x), I(x′), I(y), (II), (IIa), (IIb), (IIIa),(IIIb), (IVa), (IVb), (V), (VI), (Via), (VII), (VIIa), (VIIb), (VIIc),(VIId), (VIId′), (VIIe), (VIIe′), (a), (b), (ba), (bb), (bc) or (c)) andany example also includes the salts or tautomers or solvates thereof.

Salts

Many compounds of the formula (I) can exist in the form of salts, forexample acid addition salts or, in certain cases salts of organic andinorganic bases such as carboxylate, sulfonate and phosphate salts. Allsuch salts are within the scope of this invention, and references tocompounds of the formula (I) include the salt forms of the compounds.

The salts of the present invention can be synthesized from the parentcompound that contains a basic or acidic moiety by conventional chemicalmethods such as methods described in Pharmaceutical Salts: Properties,Selection, and Use, P. Heinrich Stahl (Editor), Camille G. Wermuth(Editor), ISBN: 3-90639-026-8, Hardcover, 388 pages, August 2002.Generally, such salts can be prepared by reacting the free acid or baseforms of these compounds with the appropriate base or acid in water orin an organic solvent, or in a mixture of the two; generally, nonaqueousmedia such as ether, ethyl acetate, ethanol, isopropanol, oracetonitrile are used.

Acid addition salts (mono- or di-salts) may be formed with a widevariety of acids, both inorganic and organic. Examples of acid additionsalts include mono- or di-salts formed with an acid selected fromacetic, 2,2-dichloroacetic, adipic, alginic, ascorbic (e.g. L-ascorbic),L-aspartic, benzenesulfonic, benzoic, 4-acetamidobenzoic, butanoic, (+)camphoric, camphor-sulfonic, (+)-(1S)-camphor-10-sulfonic, capric,caproic, caprylic, cinnamic, citric, cyclamic, dodecylsulfuric,ethane-1,2-disulfonic, ethanesulfonic, 2-hydroxyethanesulfonic, formic,fumaric, galactaric, gentisic, glucoheptonic, D-gluconic, glucuronic(e.g. D-glucuronic), glutamic (e.g. L-glutamic), α-oxoglutaric,glycolic, hippuric, hydrohalic acids (e.g. hydrobromic, hydrochloric,hydriodic), isethionic, lactic (e.g. (+)-L-lactic, (±)-DL-lactic),lactobionic, maleic, malic, (−)-L-malic, malonic, (±)-DL-mandelic,methanesulfonic, naphthalene-2-sulfonic, naphthalene-1,5-disulfonic,1-hydroxy-2-naphthoic, nicotinic, nitric, oleic, orotic, oxalic,palmitic, pamoic, phosphoric, propionic, pyruvic, L-pyroglutamic,salicylic, 4-amino-salicylic, sebacic, stearic, succinic, sulfuric,tannic, (+)-L-tartaric, thiocyanic, p-toluenesulfonic, undecylenic andvaleric acids, as well as acylated amino acids and cation exchangeresins.

One particular group of salts consists of salts formed from acetic,hydrochloric, hydriodic, phosphoric, nitric, sulfuric, citric, lactic,succinic, maleic, malic, isethionic, fumaric, benzenesulfonic,toluenesulfonic, methanesulfonic (mesylate), ethanesulfonic,naphthalenesulfonic, valeric, acetic, propanoic, butanoic, malonic,glucuronic and lactobionic acids. One particular salt is thehydrochloride salt.

In one embodiment the compound is the tris(hydroxymethyl)aminomethane(TRIS) salt.

If the compound is anionic, or has a functional group which may beanionic (e.g., —COOH may be —COO—), then a salt may be formed with anorganic or inorganic base, generating a suitable cation. Examples ofsuitable inorganic cations include, but are not limited to, alkali metalions such as Li⁺, Na⁺ and K⁺, alkaline earth metal cations such as Ca²⁺and Mg²⁺, and other cations such as Al³⁺ or Zn⁺. Examples of suitableorganic cations include, but are not limited to, ammonium ion (i.e., NH₄⁺) and substituted ammonium ions (e.g., NH₃R⁺, NH₂R₂ ⁺, NHR₃ ⁺, NR₄ ⁺).Examples of some suitable substituted ammonium ions are those derivedfrom: methylamine, ethylamine, diethylamine, propylamine,dicyclohexylamine, triethylamine, butylamine, ethylenediamine,ethanolamine, diethanolamine, piperazine, benzylamine,phenylbenzylamine, choline, meglumine, and tromethamine, as well asamino acids, such as lysine and arginine. An example of a commonquaternary ammonium ion is N(CH₃)₄ ⁺.

Where the compounds of the formula (I) contain an amine function, thesemay form quaternary ammonium salts, for example by reaction with analkylating agent according to methods well known to the skilled person.Such quaternary ammonium compounds are within the scope of formula (I).

The compounds of the invention may exist as mono- or di-salts dependingupon the pKa of the acid from which the salt is formed.

The salt forms of the compounds of the invention are typicallypharmaceutically acceptable salts, and examples of pharmaceuticallyacceptable salts are discussed in Berge et al., 1977, “PharmaceuticallyAcceptable Salts,” J. Pharm. Sci., Vol. 66, pp. 1-19. However, saltsthat are not pharmaceutically acceptable may also be prepared asintermediate forms which may then be converted into pharmaceuticallyacceptable salts. Such non-pharmaceutically acceptable salt forms, whichmay be useful, for example, in the purification or separation of thecompounds of the invention, also form part of the invention.

In one embodiment of the invention, there is provided a pharmaceuticalcomposition comprising a solution (e.g. an aqueous solution) containinga compound of the formula (I) and sub-groups and examples thereof asdescribed herein in the form of a salt in a concentration of greaterthan 10 mg/ml, typically greater than 15 mg/ml and typically greaterthan 20 mg/ml.

N-Oxides

Compounds of the formula (I) containing an amine function may also formN-oxides. A reference herein to a compound of the formula (I) thatcontains an amine function also includes the N-oxide.

Where a compound contains several amine functions one, or more than one,nitrogen atom may be oxidised to form an N-oxide. Particular examples ofN-oxides are the N-oxides of a tertiary amine or a nitrogen atom of anitrogen-containing heterocyclylic group.

N-Oxides can be formed by treatment of the corresponding amine with anoxidizing agent such as hydrogen peroxide or a per-acid (e.g. aperoxycarboxylic acid), see for example Advanced Organic Chemistry, byJerry March, 4^(th) Edition, Wiley Interscience, pages. Moreparticularly, N-oxides can be made by the procedure of L. W. Deady (Syn.Comm. 1977, 7, 509-514) in which the amine compound is reacted withm-chloroperoxybenzoic acid (MCPBA), for example, in an inert solventsuch as dichloromethane.

In one embodiment of the invention, the compound is an N-oxide, e.g.from a nitrogen atom on the R⁶ or R⁷ group, for example a pyridineN-oxide.

Geometric Isomers and Tautomers

Compounds of the formula (I) may exist in a number of differentgeometric isomeric, and tautomeric forms and references to compounds ofthe formula (I) include all such forms. For the avoidance of doubt,where a compound can exist in one of several geometric isomeric ortautomeric forms and only one is specifically described or shown, allothers are nevertheless embraced by formula (I).

For example, certain heteroaryl rings can exist in the two tautomericforms such as A and B shown below. For simplicity, a formula mayillustrate one form but the formula is to be taken as embracing bothtautomeric forms.

Other examples of tautomeric forms include, for example, keto-, enol-,and enolate-forms, as in, for example, the following tautomeric pairs:keto/enol (illustrated below), imine/enamine, amide/imino alcohol,amidine/enediamines, nitroso/oxime, thioketone/enethiol, andnitro/aci-nitro.

Stereoisomers

Unless otherwise mentioned or indicated, the chemical designation ofcompounds denotes the mixture of all possible stereochemically isomericforms.

Stereocentres are illustrated in the usual fashion, using ‘hashed’ or‘solid’ wedged lines. e.g.

Where a compound is described as a mixture of twodiastereoisomers/epimers, the configuration of the stereocentre is notspecified and is represented by straight lines.

Where compounds of the formula (I) contain one or more chiral centres,and can exist in the form of two or more optical isomers, references tocompounds of the formula (I) include all optical isomeric forms thereof(e.g. enantiomers, epimers and diastereoisomers), either as individualoptical isomers, or mixtures (e.g. racemic or scalemic mixtures) or twoor more optical isomers, unless the context requires otherwise.

The optical isomers may be characterised and identified by their opticalactivity (i.e. as + and − isomers, or d and l isomers) or they may becharacterised in terms of their absolute stereochemistry using the “Rand S” nomenclature developed by Cahn, Ingold and Prelog, see AdvancedOrganic Chemistry by Jerry March, 4^(th) Edition, John Wiley & Sons, NewYork, 1992, pages 109-114, and see also Cahn, Ingold & Prelog, Angew.Chem. Int. Ed. Engl., 1966, 5, 385-415.

Optical isomers can be separated by a number of techniques includingchiral chromatography (chromatography on a chiral support) and suchtechniques are well known to the person skilled in the art.

As an alternative to chiral chromatography, optical isomers can beseparated by forming diastereoisomeric salts with chiral acids such as(+)-tartaric acid, (−)-pyroglutamic acid, (−)-di-toluoyl-L-tartaricacid, (+)-mandelic acid, (−)-malic acid, and (−)-camphorsulfonic acid,separating the diastereoisomers by preferential crystallisation, andthen dissociating the salts to give the individual enantiomer of thefree base.

Additionally enantiomeric separation can be achieved by covalentlylinking a enantiomerically pure chiral auxiliary onto the compound andthen performing diastereoisomer separation using conventional methodssuch as chromatography. This is then followed by cleavage of theaforementioned covalent linkage to generate the appropriateenantiomerically pure product.

Where compounds of the formula (I) exist as two or more optical isomericforms, one enantiomer in a pair of enantiomers may exhibit advantagesover the other enantiomer, for example, in terms of biological activity.Thus, in certain circumstances, it may be desirable to use as atherapeutic agent only one of a pair of enantiomers, or only one of aplurality of diastereoisomers.

Accordingly, the invention provides compositions containing a compoundof the formula (I) having one or more chiral centres, wherein at least55% (e.g. at least 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95%) of thecompound of the formula (I) is present as a single optical isomer (e.g.enantiomer or diastereoisomer). In one general embodiment, 99% or more(e.g. substantially all) of the total amount of the compound of theformula (I) may be present as a single optical isomer (e.g. enantiomeror diastereoisomer).

Compounds encompassing double bonds can have an E (entgegen) or Z(zusammen) stereochemistry at said double bond. Substituents on bivalentcyclic or (partially) saturated radicals may have either the cis- ortrans-configuration. The terms cis and trans when used herein are inaccordance with Chemical Abstracts nomenclature (J. Org. Chem. 1970, 35(9), 2849-2867), and refer to the position of the substituents on a ringmoiety.

Of special interest are those compounds of formula (I) which arestereochemically pure. When a compound of formula (I) is for instancespecified as R, this means that the compound is substantially free ofthe S isomer. If a compound of formula (I) is for instance specified asE, this means that the compound is substantially free of the Z isomer.The terms cis, trans, R, S, E and Z are well known to a person skilledin the art.

Isotopic Variations

The present invention includes all pharmaceutically acceptableisotopically-labeled compounds of the invention, i.e. compounds offormula (I), wherein one or more atoms are replaced by atoms having thesame atomic number, but an atomic mass or mass number different from theatomic mass or mass number usually found in nature.

Examples of isotopes suitable for inclusion in the compounds of theinvention comprise isotopes of hydrogen, such as ²H (D) and ³H (T),carbon, such as ¹¹C, ¹³C and ¹⁴C, chlorine, such as ³⁶Cl, fluorine, suchas ¹⁸F, iodine, such as ¹²³I, ¹²⁵I and ¹³¹I, nitrogen, such as ¹³N and¹⁵N, oxygen, such as 150, 170 and ¹⁸O, phosphorus, such as ³²P, andsulfur, such as ³⁵S.

Certain isotopically-labelled compounds of formula (I), for example,those incorporating a radioactive isotope, are useful in drug and/orsubstrate tissue distribution studies. The compounds of formula (I) canalso have valuable diagnostic properties in that they can be used fordetecting or identifying the formation of a complex between a labelledcompound and other molecules, peptides, proteins, enzymes or receptors.The detecting or identifying methods can use compounds that are labelledwith labelling agents such as radioisotopes, enzymes, fluorescentsubstances, luminous substances (for example, luminol, luminolderivatives, luciferin, aequorin and luciferase), etc. The radioactiveisotopes tritium, i.e. ³H (T), and carbon-14, i.e. ¹⁴C, are particularlyuseful for this purpose in view of their ease of incorporation and readymeans of detection.

Substitution with heavier isotopes such as deuterium, i.e. ²H (D), mayafford certain therapeutic advantages resulting from greater metabolicstability, for example, increased in vivo half-life or reduced dosagerequirements, and hence may be used in some circumstances.

In particular, every reference to hydrogen in the application should beconstructed to cover ¹H and ²H, whether hydrogen is defined explicitly,or hydrogen is present implicitly to satisfy the relevant atom's (inparticular carbon's) valency.

Substitution with positron emitting isotopes, such as ¹¹C, ¹⁸F, ¹⁵O and¹³N, can be useful in Positron Emission Topography (PET) studies forexamining target occupancy.

Isotopically-labeled compounds of formula (I) can generally be preparedby conventional techniques known to those skilled in the art or byprocesses analogous to those described in the accompanying Examples andPreparations using an appropriate isotopically-labeled reagents in placeof the non-labeled reagent previously employed.

Esters

Esters such as carboxylic acid esters, acyloxy esters and phosphateesters of the compounds of formula (I) bearing a carboxylic acid groupor a hydroxyl group are also embraced by Formula (I). Examples of estersare compounds containing the group —C(═O)OR, wherein R is an estersubstituent, for example, a C₁₋₇ alkyl group, a C₃₋₁₂ heterocyclylgroup, or a C₅₋₁₂ aryl group, typically a C₁₋₆ alkyl group. Particularexamples of ester groups include, but are not limited to, —C(═O)OCH₃,—C(═O)OCH₂CH₃, —C(═O)OC(CH₃)₃, and —C(═O)OPh. Examples of acyloxy(reverse ester) groups are represented by —OC(═O)R, wherein R is anacyloxy substituent, for example, a C₁₋₆ alkyl group, a C₃₋₁₂heterocyclyl group, or a C₅₋₁₂ aryl group, typically a C₁₋₆ alkyl group.Particular examples of acyloxy groups include, but are not limited to,—OC(═O)CH₃ (acetoxy), —OC(═O)CH₂CH₃, —OC(═O)C(CH₃)₃, —OC(═O)Ph, and—OC(═O)CH₂Ph. Examples of phosphate esters are those derived fromphosphoric acid.

In one embodiment of the invention, formula (I) includes within itsscope esters of compounds of the formula (I) bearing a carboxylic acidgroup or a hydroxyl group. In another embodiment of the invention,formula (I) does not include within its scope esters of compounds of theformula (I) bearing a carboxylic acid group or a hydroxyl group.

Solvates and Crystalline Forms

Also encompassed by formula (I) are any polymorphic forms of thecompounds, and solvates such as hydrates, alcoholates and the like.

The compounds of the invention may form solvates, for example with water(i.e., hydrates) or common organic solvents. As used herein, the term“solvate” means a physical association of the compounds of the presentinvention with one or more solvent molecules. This physical associationinvolves varying degrees of ionic and covalent bonding, includinghydrogen bonding. In certain instances the solvate will be capable ofisolation, for example when one or more solvent molecules areincorporated in the crystal lattice of the crystalline solid. The term“solvate” is intended to encompass both solution-phase and isolatablesolvates. Non-limiting examples of suitable solvates include compoundsof the invention in combination with water, isopropanol, ethanol,methanol, DMSO, ethyl acetate, acetic acid or ethanolamine and the like.The compounds of the invention may exert their biological effects whilstthey are in solution.

Solvates are well known in pharmaceutical chemistry. They can beimportant to the processes for the preparation of a substance (e.g. inrelation to their purification, the storage of the substance (e.g. itsstability) and the ease of handling of the substance and are oftenformed as part of the isolation or purification stages of a chemicalsynthesis. A person skilled in the art can determine by means ofstandard and long used techniques whether a hydrate or other solvate hasformed by the isolation conditions or purification conditions used toprepare a given compound. Examples of such techniques includethermogravimetric analysis (TGA), differential scanning calorimetry(DSC), X-ray crystallography (e.g. single crystal X-ray crystallographyor X-ray powder diffraction) and Solid State NMR (SS-NMR, also known asMagic Angle Spinning NMR or MAS-NMR). Such techniques are as much a partof the standard analytical toolkit of the skilled chemist as NMR, IR,HPLC and MS.

Alternatively the skilled person can deliberately form a solvate usingcrystallisation conditions that include an amount of the solventrequired for the particular solvate. Thereafter the standard methodsdescribed herein, can be used to establish whether solvates had formed.

Furthermore, the compounds of the present invention may have one or morepolymorph or amorphous crystalline forms and as such are intended to beincluded in the scope of the invention.

Complexes

Formula (I) also includes within its scope complexes (e.g. inclusioncomplexes or clathrates with compounds such as cyclodextrins, orcomplexes with metals) of the compounds. Inclusion complexes, clathratesand metal complexes can be formed by means of methods well known to theskilled person.

Prodrugs

Also encompassed by formula (I) are any pro-drugs of the compounds ofthe formula (I). By “prodrugs” is meant for example any compound that isconverted in vivo into a biologically active compound of the formula(I).

For example, some prodrugs are esters of the active compound (e.g., aphysiologically acceptable metabolically labile ester). Duringmetabolism, the ester group (—C(═O)OR) is cleaved to yield the activedrug. Such esters may be formed by esterification, for example, of anyof the carboxylic acid groups (—C(═O)OH) in the parent compound, with,where appropriate, prior protection of any other reactive groups presentin the parent compound, followed by deprotection if required.

Examples of such metabolically labile esters include those of theformula —C(═O)OR wherein R is:

C₁₋₇alkyl (e.g., -Me, -Et, -nPr, -iPr, -nBu, -sBu, -iBu, -tBu);

C₁₋₇aminoalkyl (e.g., aminoethyl; 2-(N,N-diethylamino)ethyl;2-(4-morpholino)ethyl); and acyloxy-C₁₋₇alkyl (e.g., acyloxymethyl;acyloxyethyl; pivaloyloxymethyl; acetoxymethyl; 1-acetoxyethyl;1-(1-methoxy-1-methyl)ethyl-carbonxyloxyethyl; 1-(benzoyloxy)ethyl;isopropoxy-carbonyloxymethyl; 1-isopropoxy-carbonyloxyethyl;cyclohexyl-carbonyloxymethyl; 1-cyclohexyl-carbonyloxyethyl;cyclohexyloxy-carbonyloxymethyl; 1-cyclohexyloxy-carbonyloxyethyl;(4-oxanyloxy) carbonyloxymethyl; 1-(4-oxanyloxy)carbonyloxyethyl;(4-oxanyl)carbonyloxymethyl; and1-(4-tetrahydropyranyl)carbonyloxyethyl).

Also, some prodrugs are activated enzymatically to yield the activecompound, or a compound which, upon further chemical reaction, yieldsthe active compound (for example, as in antigen-directed enzyme pro-drugtherapy (ADEPT), gene-directed enzyme pro-drug therapy (GDEPT), andligand-directed enzyme pro-drug therapy (LIDEPT), etc.). For example,the prodrug may be a sugar derivative or other glycoside conjugate, ormay be an amino acid ester derivative. In one embodiment formula (I)does not include pro-drugs of the compounds of the formula (I) withinits scope.

Methods for the Preparation of Compounds of Formula (I)

In this section, as in all other sections of this application unless thecontext indicates otherwise, references to formula (I) also include allother subformula (e.g. formulae I(c), I(f), I(g), I(g′), I(h), I(i),I(j), I(k), I(L), I(m), I(m′), I(n), I(o), I(o′), I(o″), I(p), I(p′),I(q), I(q′), I(q″), I(q′″), (q″″), I(r), I(s), I(t), I(u), I(v), I(v′),I(w), I(x), I(x′), I(y), (II), (IIa), (IIb), (IIIa), (IIIb), (IVa),(IVb), (V), (VI), (Via), (VII), (VIIa), (VIIb), (VIIc), (VIId), (VIId′),(VIIe), (Vile′), (a), (b), (ba), (bb), (bc) or (c)) and examples thereofas defined herein, unless the context indicates otherwise.

Compounds of the formula (I) can be prepared in accordance withsynthetic methods well known to the skilled person.

According to a further aspect of the invention there is provided aprocess for preparing a compound of formula (I), or a tautomer,stereoisomer, N-oxide, pharmaceutically acceptable salt, or solvatethereof which comprises:

According to a further aspect of the invention there is provided aprocess for preparing a compound of formula (I) as hereinbefore definedwhich comprises:

(a) reacting a compound of formula (XV) with an organometallic reagentof the formula R⁷M (where M is a metal), for example a Grignard reagentof the formula R⁷MgBr:

wherein R¹, R², R³, R⁴, R⁵, R⁶, a, s m and n are as defined herein;

(b) interconversion of a compound of formula (I) or protected derivativethereof to a further compound of formula (I) or protected derivativethereof; and/or

(c) deprotection of a protected derivative of a compound of formula (I);and/or

(d) providing a compound of formula (I) and forming a pharmaceuticallyacceptable salt of the compound.

The required intermediates are either commercially available, known inthe literature, prepared by methods analogous to those in the literatureor prepared by methods analogous to those described in the exampleexperimental procedures below. Other compounds may be prepared byfunctional group interconversion of the groups using methods well knownin the art.

The general synthetic route for the preparation of compounds of formulaXV, a key intermediate is set out in the Schemes below.

Example reagents and conditions for Scheme 1: a) NaOH, H₂O, CHCl₃, 85°C.; A) AcOH, rt; B) Pb(OAc)₄, THF, 0° C.; C) NaClO₂, H₂NSO₃H, CH₃CN,H₂O, rt; D) i) SOCl₂, DMF, THF, ii) amine, i-Pr₂EtN, THF; E) i) SOCl₂,DMF, THF, ii) R³(CH₂)_(s)—OH, K₂CO₃, THF; F) InBr₃, R³(CH₂)_(s)—OH, DCE,85° C.; separation and isolation of the 3(R) enantiomer can be achievedat this stage by chiral HPLC.

In Scheme 1, R¹, R², R³, R⁴ and R⁵ are as described herein and Wrepresents a leaving group, such as for example halo, e.g. bromo, or acarbonyl group, such as for example acetyl.

N-aroylhydrazone (XI) can be prepared by condensing benzaldehyde (IX)with benzohydrazide (X). Reaction with Pb(OAc)₄ yields aldehyde (XII),from which a Pinnick oxidation provides acid (XIII). The appropriatebenzylamine can then be used to provide 3-hydroxyisoindolinone (XIV),and the R³—containing side chain added using thionyl chloride or InBr₃and the appropriate alcohol.

Intermediates of formula (XV) can be used as a starting point for thesynthesis of compounds of the present invention having varyingfunctionality in the R³, R⁶ and R⁷ positions of Formula I.

Scheme 2 below sets out example procedures for introducing various R⁶moieties starting from intermediates of formula (XVI) (which is thecompound of formula (XV) wherein W is Br).

Example reagents and conditions for Scheme 2: G) (i) toluene,1,4-dioxane, LiCl, tributyl(1-ethoxyvinyl)tin, Pd(PPh₃)₄, (ii) HCl,H₂O/THF. H) MeMgCl, in the presence of ZnCl₂ and/or LaCl₃-2LiCl, THF.Separation and isolation of the 3(R) enantiomer can be achieved at anystage by chiral HPLC.

Bromide (XVI) can be converted to methyl ketone (XVII) for example using1,4-dioxane, LiCl, tributyl(1-ethoxyvinyl)tin, Pd(PPh₃)₄, and furtherconverted to the alcohol XVIII by reaction with a methyl Grignardreagent.

Compounds wherein R⁶ and R⁷ are hydrogen, can also be prepared accordingto the general synthetic Scheme 3. Where R³ contains a hydroxyl group,this can be protected during the synthesis by using standard protectinggroups (e.g. TBDMS, TBDPS). Deprotection can be performed using standardconditions (e.g. TBAF).

Example reagents and conditions for Scheme 3: I) HCOOLi.H₂O, Ac₂O, Et₃N,4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene, Pd(OAc)₂, DMF; J)LiBH₄, THF.

Compounds of formula (XVIII), first shown in Scheme 2, wherein R⁶ and R⁷are methyl, can also be prepared according to the general syntheticScheme 4.

In Scheme 4, an intermediate of formula (XXIV) is prepared from anintermediate of formula (XXIII) according to procedure F (InBr₃ withR³(CH₂)_(s)—OH). The intermediate of formula (XXIV) is then converted tothe compound of formula (XVIII) by a Grignard reaction.

Example reagents and conditions: F) InBr₃ R³(CH₂)_(s)—OH, DCE, 85° C.;H) MeMgCl, ZnCl₂, THF, 0° C. Separation and isolation of the 3(R)enantiomer can be achieved at stage F or H by chiral HPLC.

Compounds of general formula XXX can also be prepared according toSchemes 5 and 6.

Example reagents and conditions: L) nBuLi, Het-CHO, THF, −78° C.; M)MnO₂, MeCN, or I₂, KI, K₂CO₃; D) i) SOCl₂, DMF, THF, ii) amine,i-Pr₂EtN, THF or HATU, amine, DIPEA, DMF; E) i) SOCl₂, DMF, THF, ii)R³(CH₂)_(s)—OH, K₂CO₃, THF; F) InBr₃, R³(CH₂)_(s)—OH, DCE, 85° C.; N)R₇MgX in the presence of ZnCl₂ and/or LaCl₃-2LiCl, THF or Al(R₇)₃, THFor EtLi, ZnEt₂, THF. Separation of enantiomers and/or diastereoisomersat Stages E, F and N can be achieved by either chiral and/or achiralHPLC.

Intermediate XIII (where W is Br) is reacted with nBuLi and anappropriate aldehyde to provide alcohol XXVI which is oxidised to thecorresponding ketone (XXVII) either using MnO₂ or I₂/KI. IntermediateXXVII is then converted into the 3-hydroxyisoindolinone XXIX followingprocedures D and E (of F) described above.

Intermediates of formula XXIX can be used as a starting point for thesynthesis of compounds of the present invention having varyingfunctionality in the R⁷ position of Formula I

Alternatively the R⁷ substituents are introduced earlier in thesynthesis as shown in Scheme 6. Intermediates of formula XXVII can reactwith organometallic reagents to provide tertiary alcohol (XXXI) which isthen converted to final compounds of Formula I following procedures Dand E (or F) (Scheme 6).

Example reagents and conditions: N) R₇MgX in the presence of ZnCl₂and/or LaCl₃-2LiCl, THF or Al(R₇)₃, THF or EtLi, ZnEt₂, THF; D) i)SOCl₂, DMF, THF, ii) amine, i-Pr₂EtN, THF or HATU, amine, DIPEA, DMF; E)i) SOCl₂, DMF, THF, ii) R³(CH₂)_(s)—OH, K₂CO₃, THF; F) InBr₃R³(CH₂)_(s)—OH, DCE, 85° C. Separation of enantiomers and/ordiastereoisomers at Stages N and E/F can be achieved by either chiraland/or achiral HPLC.

Compounds of formula XVI (first shown in Scheme 2) can also be used tomake compounds of formula XXIX using methods outlined in Scheme 7. Inthis case, XVI can be converted into a suitable boronate using, forexample, Miyaura conditions. The boronate is then treated with anappropriate heterocyclic iodide (or heterocyclic bromide) in thepresence of carbon monoxide, a suitable catalyst (such as Pd(dppf)Cl₂.)and a solvent (such as toluene or ansole).

Alternatively, compounds of formula XVI can be treated with anappropriate heterocyclic stannane in the presence of carbon monoxide, asuitable catalyst [such as Pd(dppf)Cl₂] and a solvent (such as DMF) togive compounds of formula XXIX (Scheme 7). Separation and isolation ofthe 3(R) intermediate can be achieved at any stage using chiral HPLC.Compounds of formula XXIX can then be progressed to compounds of formulaXXX (as shown in Scheme 5),

Compounds of formula XVI can also be used to make compounds of formulaXXIX using methods outlined in Scheme 8. In this case, compounds offormula XVI can be used to make a Weinreb amide derivative usingN,O-dimethylhydroxylamine hydrochloride in the presence of carbonmonoxide and a suitable palladium catalyst (e.g. Xantphos G3 catalyst).The Weinreb amide can then be reacted with an appropriate metallatedheterocycle (e.g. the product of 4-bromo-1-methyl-1H-pyrazole and nBuLiin THF) to give compounds of formula XXIX (Scheme 8). Separation andisolation of the 3(R) intermediate can be achieved at any stage usingchiral HPLC. Compounds of formula XXIX can then be progressed tocompounds of formula XXX (as shown in Scheme 5).

It will be appreciated that certain compounds can exist in differentdiastereomeric and/or enantiomeric forms and that processes for theirpreparation may make use of enantiomerically pure synthetic precursors.

Alternatively racemic precursors may be used and the mixtures ofdiastereoisomers generated in these process may be separated by methodswell known to the person skilled in the art, for example usingnon-chiral or chiral preparative chromatography or resolution usingdiastereomeric derivatives: for example crystallisation of a salt formedwith an enantiomerically pure acid such as L-tartaric acid (orenantiomerically pure base such as (1R)-1-phenylethan-1-amine); orenantiomer separation of a diastereomeric derivative formed bycovalently linking a enantiomerically pure chiral auxiliary onto thecompound, followed by separation using conventional methods such aschiral or non-chiral chromatography. The aforementioned covalent linkageis then cleaved to generate the appropriate enantiomerically pureproduct.

A wide range of well known functional group interconversions are knownby a person skilled in the art for converting a precursor compound to acompound of formula I and are described in Advanced Organic Chemistry byJerry March, 4^(th) Edition, John Wiley & Sons, 1992. For examplepossible metal catalysed functionalisations such as using organo-tinreagents (the Stille reaction), Grignard reagents and reactions withnitrogen nucleophiles are described in ‘Palladium Reagents andCatalysts’ [Jiro Tsuji, Wiley, ISBN 0-470-85032-9] and Handbook ofOrganoPalladium Chemistry for Organic Synthesis [Volume 1, Edited byEi-ichi Negishi, Wiley, ISBN 0-471-31506-0].

If appropriate, the reactions previously described below are followed orpreceded by one or more reactions known to the skilled of the art andare performed in an appropriate order to achieve the requisitesubstitutions defined above to afford other compounds of formula (I).Non-limiting examples of such reactions whose conditions can be found inthe literature include:

-   -   protection of reactive functions,    -   deprotection of reactive functions,    -   halogenation,    -   dehalogenation,    -   dealkylation,    -   alkylation or arylation of amine, aniline, alcohol and phenol,    -   Mitsunobu reaction on hydroxyl groups,    -   cycloaddition reactions on appropriate groups,    -   reduction of nitro, esters, cyano, aldehydes,    -   transition metal-catalyzed coupling reactions,    -   acylation,    -   sulfonylation/introduction of sulfonyl groups,    -   saponification/hydrolysis of ester groups,    -   amidification or transesterification of ester groups,    -   esterification or amidification of carboxylic groups,    -   halogen exchange,    -   nucleophilic substitution with amine, thiol or alcohol,    -   reductive amination,    -   oxime formation on carbonyl and hydroxylamine groups,    -   S-oxidation,    -   N-oxidation,    -   salification.

It will be appreciated that certain compounds e.g. compounds of formulae(I), I(c), I(f), I(g), I(g′), I(h), I(i), I(j), I(k), I(L), I(m), I(m′),I(n), I(o), I(o′), I(o″), I(p), I(p′), I(q), I(q′), I(q″), I(q′″),I(q″″), I(r), I(s), I(t), I(u), I(v), I(v′), I(w), I(x), I(x′), I(y),(II), (IIa), (IIb), (IIIa), (IIIb), (IVa), (IVb), (V), (VI), (Via),(VII), (VIIa), (VIIb), (VIIc), (VIId), (VIId′), (VIIe), (VIIe′), (a),(b), (ba), (bb), (bc) or (c) can exist in different diastereomericand/or enantiomeric forms and that processes for their preparation maymake use of enantiomerically pure synthetic precursors.

Alternatively racemic precursors may be used and the mixtures ofdiastereoisomers generated in these process may be separated by methodswell known to the person skilled in the art, for example usingnon-chiral or chiral preparative chromatography or resolution usingdiastereomeric derivatives: for example crystallisation of a salt formedwith an enantiomerically pure acid such as L-tartaric acid; orenantiomer separation of a diastereomeric derivative formed bycovalently linking a enantiomerically pure chiral auxiliary onto thecompound, followed by separation using conventional methods such aschiral chromatography. The aforementioned covalent linkage is thencleaved to generate the appropriate enantiomerically pure product.

Certain of the required intermediates, are either commerciallyavailable, known in the literature, prepared by methods analogous tothose in the literature or prepared by methods analogous to thosedescribed in the example experimental procedures below. Other compoundsmay be prepared by functional group interconversion using methods wellknown in the art.

In a further embodiment the invention provides a novel intermediate. Inone embodiment the invention provides a novel intermediate of (VII),(VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII),(XIX), (XX), (XXI), (XXIII) and (XXIV).

Protecting Groups

In many of the reactions described herein, it may be necessary toprotect one or more groups to prevent reaction from taking place at anundesirable location on the molecule. Examples of protecting groups, andmethods of protecting and deprotecting functional groups, can be foundin Protective Groups in Organic Synthesis (T. Green and P. Wuts; 3rdEdition; John Wiley and Sons, 1999).

In particular the compound may be synthesised in protected forms and theprotecting groups removed to generate a compound of formula (I).

A hydroxy group may be protected, for example, as an ether (—OR) or anester (—OC(═O)R), for example, as: a t-butyl ether; a tetrahydropyranyl(THP) ether; a benzyl, benzhydryl (diphenylmethyl), or trityl(triphenylmethyl) ether; a trimethylsilyl or t-butyldimethylsilyl ether;or an acetyl ester (—OC(═O)CH₃).

An aldehyde or ketone group may be protected, for example, as an acetal(R—CH(OR)₂) or ketal (R₂C(OR)₂), respectively, in which the carbonylgroup (>C═O) is treated with, for example, a primary alcohol. Thealdehyde or ketone group is readily regenerated by hydrolysis using alarge excess of water in the presence of acid.

An amine group may be protected, for example, as an amide (—NRCO—R) or acarbamate (—NRCO—OR), for example, as: a methyl amide (—NHCO—CH₃); abenzyl carbamate (—NHCO—OCH₂C₆H₅, —NH-Cbz or NH—Z); as a t-butylcarbamate (—NHCO—OC(CH₃)₃, —NH-Boc); a 2-biphenyl-2-propyl carbamate(—NHCO—OC(CH₃)₂C₆H₄C₆H₅, —NH-Bpoc), as a 9-fluorenylmethyl carbamate(—NH-Fmoc), as a 6-nitroveratryl carbamate (—NH-Nvoc), as a2-trimethylsilylethyl carbamate (—NH-Teoc), as a 2,2,2-trichloroethylcarbamate (—NH-Troc), as an allyl carbamate (—NH-Alloc), or as a2(-phenylsulfonyl)ethyl carbamate (—NH-Psec).

Other protecting groups for amines, such as cyclic amines andheterocyclic N—H groups, include toluenesulfonyl (tosyl) andmethanesulfonyl (mesyl) groups, benzyl groups such as apara-methoxybenzyl (PMB) group and tetrahydropyranyl (THP) groups.

A carboxylic acid group may be protected as an ester for example, as: anC₁₋₇ alkyl ester (e.g., a methyl ester; a t-butyl ester); a C₁₋₇haloalkyl ester (e.g., a C₁₋₇ trihaloalkyl ester); a triC₁₋₇alkylsilyl-C₁₋₇alkyl ester; or a C₅₋₂₀ aryl-C₁₋₇ alkyl ester (e.g., abenzyl ester; a nitrobenzyl ester; para-methoxybenzyl ester. A thiolgroup may be protected, for example, as a thioether (—SR), for example,as: a benzyl thioether; an acetamidomethyl ether (—S—CH₂NHC(═O)CH₃).

Isolation and Purification of the Compounds of the Invention

The compounds of the invention can be isolated and purified according tostandard techniques well known to the person skilled in the art andexamples of such methods include chromatographic techniques such ascolumn chromatography (e.g. flash chromatography) and HPLC. Onetechnique of particular usefulness in purifying the compounds ispreparative liquid chromatography using mass spectrometry as a means ofdetecting the purified compounds emerging from the chromatographycolumn.

Preparative LC-MS is a standard and effective method used for thepurification of small organic molecules such as the compounds describedherein. The methods for the liquid chromatography (LC) and massspectrometry (MS) can be varied to provide better separation of thecrude materials and improved detection of the samples by MS.Optimisation of the preparative gradient LC method will involve varyingcolumns, volatile eluents and modifiers, and gradients. Methods are wellknown in the art for optimising preparative LC-MS methods and then usingthem to purify compounds. Such methods are described in Rosentreter U,Huber U.; Optimal fraction collecting in preparative LC/MS; J CombChem.; 2004; 6(2), 159-64 and Leister W, Strauss K, Wisnoski D, Zhao Z,Lindsley C., Development of a custom high-throughput preparative liquidchromatography/mass spectrometer platform for the preparativepurification and analytical analysis of compound libraries; J CombChem.; 2003; 5(3); 322-9. An example of such a system for purifyingcompounds via preparative LC-MS is described below in the Examplessection of this application (under the heading “Mass DirectedPurification LC-MS System”).

Methods of recrystallisation of compounds of formula (I) and saltthereof can be carried out by methods well known to the skilledperson—see for example (P. Heinrich Stahl (Editor), Camille G.

Wermuth (Editor), ISBN: 3-90639-026-8, Handbook of Pharmaceutical Salts:Properties, Selection, and Use, Chapter 8, Publisher Wiley-VCH).Products obtained from an organic reaction are seldom pure when isolateddirectly from the reaction mixture. If the compound (or a salt thereof)is solid, it may be purified and/or crystallized by recrystallisationfrom a suitable solvent. A good recrystallisation solvent shoulddissolve a moderate quantity of the substance to be purified at elevatedtemperatures but only a small quantity of the substance at lowertemperature. It should dissolve impurities readily at low temperaturesor not at all. Finally, the solvent should be readily removed from thepurified product. This usually means that it has a relatively lowboiling point and a person skilled in the art will know recrystallisingsolvents for a particular substance, or if that information is notavailable, test several solvents. To get a good yield of purifiedmaterial, the minimum amount of hot solvent to dissolve all the impurematerial is used. In practice, 3-5% more solvent than necessary is usedso the solution is not saturated. If the impure compound contains animpurity which is insoluble in the solvent it may then be removed byfiltration and then allowing the solution to crystallize. In addition,if the impure compound contains traces of coloured material that are notnative to the compound, it may be removed by adding a small amount ofdecolorizing agent e.g. activating charcoal to the hot solution,filtering it and then allowing it to crystallize. Usuallycrystallization spontaneously occurs upon cooling the solution. If it isnot, crystallization may be induced by cooling the solution below roomtemperature or by adding a single crystal of pure material (a seedcrystal). Recrystallisation can also be carried out and/or the yieldoptimized by the use of an anti-solvent or co-solvent. In this case, thecompound is dissolved in a suitable solvent at elevated temperature,filtered and then an additional solvent in which the required compoundhas low solubility is added to aid crystallization. The crystals arethen typically isolated using vacuum filtration, washed and then dried,for example, in an oven or via desiccation.

Other examples of methods for purification include sublimation, whichincludes an heating step under vacuum for example using a cold finger,and crystallization from melt (Crystallization Technology Handbook 2ndEdition, edited by A. Mersmann, 2001).

Biological Effects

It is envisaged that the compound of the invention will be useful inmedicine or therapy. The compounds of the invention, subgroups andexamples thereof, have been shown to inhibit the interaction of p53 withMDM2. Such inhibition leads to cell proliferative arrest and apoptosis,which may be useful in preventing or treating disease states orconditions described herein, for example the diseases and conditionsdiscussed below and the diseases and conditions described in the“Background of the Invention” section above in which p53 and MDM2 play arole. Thus, for example, it is envisaged that the compounds of theinvention may be useful in alleviating or reducing the incidence ofcancer.

The compounds of the present invention may be useful for the treatmentof the adult population. The compounds of the present invention may beuseful for the treatment of the pediatric population.

The compounds of the present invention have been shown to be goodinhibitors of the formation of MDM2-p53 complex. The antagonistcompounds of formula (I) are capable of binding to MDM2 and exhibitingpotency for MDM2. The efficacies of the compounds of the presentinvention have been determined against MDM2/p53 using the assay protocoldescribed herein and other methods known in the art. More particularly,the compounds of the formula (I) and sub-groups thereof have affinityfor MDM2/p53.

Certain compounds of the invention are those having IC₅₀ values of lessthan 0.1 μM in particular less than 0.01 or 0.001 μM.

MDM2/p53 function has been implicated in many diseases due to its rolein a variety of process for example vascular remodelling andantiangiogenic processes and regulation of metabolic pathways, as wellas in oncogenesis. As a consequence of their affinity for MDM2 it isanticipated that the compounds may prove useful in treating orpreventing a range of diseases or conditions including autoimmuneconditions; diabetes mellitus; chronic inflammatory diseases, forexample lupus nephritis, systemic lupus erythematosus (SLE), autoimmunemediated glomerulonephritis, rheumatoid arthritis, psoriasis,inflammatory bowel disease, autoimmune diabetes mellitus, Eczemahypersensitivity reactions, asthma, COPD, rhinitis, and upperrespiratory tract disease; hyperkeratotic diseases such as autosomalrecessive congenital ichthyosis (ARCI); kidney diseases includingglomerular disorders, chronic kidney disease (CKD) renal inflammation,podocyte loss, glomerulosclerosis, proteinuria, and progressive kidneydisease; cardiovascular diseases for example cardiac hypertrophy,restenosis, arrhythmia, atherosclerosis; ischemic injury associatedmyocardial infarctions, vascular injury, stroke and reperfusion injury;vascular proliferative diseases; ocular diseases such as age-relatedmacular degeneration in particular wet form of age-related maculardegeneration, ischemic proliferative retinopathies such as retinopathyof prematurity (ROP) and diabetic retinopathy, and hemangioma.

As a consequence of their affinity for MDM2 it is anticipated that thecompounds may prove useful in treating or preventing proliferativedisorders such as cancers.

Examples of cancers (and their benign counterparts) which may be treated(or inhibited) include, but are not limited to tumours of epithelialorigin (adenomas and carcinomas of various types includingadenocarcinomas, squamous carcinomas, transitional cell carcinomas andother carcinomas) such as carcinomas of the bladder and urinary tract,breast, gastrointestinal tract (including the esophagus, stomach(gastric), small intestine, colon, bowel, colorectal, rectum and anus),liver (hepatocellular carcinoma), gall bladder and biliary system,exocrine pancreas, kidney (for example renal cell carcinoma), lung (forexample adenocarcinomas, small cell lung carcinomas, non-small cell lungcarcinomas, bronchioalveolar carcinomas and mesotheliomas), head andneck (for example cancers of the tongue, buccal cavity, larynx, pharynx,nasopharynx, tonsil, salivary glands, nasal cavity and paranasalsinuses), ovary, fallopian tubes, peritoneum, vagina, vulva, penis,testes, cervix, myometrium, endometrium, thyroid (for example thyroidfollicular carcinoma), brain, adrenal, prostate, skin and adnexae (forexample melanoma, basal cell carcinoma, squamous cell carcinoma,keratoacanthoma, dysplastic naevus); haematological malignancies (i.e.leukemias, lymphomas) and premalignant haematological disorders anddisorders of borderline malignancy including haematological malignanciesand related conditions of lymphoid lineage (for example acutelymphocytic leukemia [ALL], chronic lymphocytic leukemia [CLL], B-celllymphomas such as diffuse large B-cell lymphoma [DLBCL], follicularlymphoma, Burkitt's lymphoma, mantle cell lymphoma, T-cell lymphomas andleukaemias, natural killer [NK] cell lymphomas, Hodgkin's lymphomas,hairy cell leukaemia, monoclonal gammopathy of uncertain significance,plasmacytoma, multiple myeloma, and post-transplant lymphoproliferativedisorders), and haematological malignancies and related conditions ofmyeloid lineage (for example acute myelogenous leukemia [AML], chronicmyelogenous leukemia [CML], chronic myelomonocytic leukemia [CMML],hypereosinophilic syndrome, myeloproliferative disorders such aspolycythaemia vera, essential thrombocythaemia and primarymyelofibrosis, myeloproliferative syndrome, myelodysplastic syndrome,and promyelocytic leukemia); tumours of mesenchymal origin, for examplesarcomas of soft tissue, bone or cartilage such as osteosarcomas,fibrosarcomas, chondrosarcomas, rhabdomyosarcomas, leiomyosarcomas,liposarcomas, angiosarcomas, Kaposi's sarcoma, Ewing's sarcoma, synovialsarcomas, epithelioid sarcomas, gastrointestinal stromal tumours, benignand malignant histiocytomas, and dermatofibrosarcoma protuberans;tumours of the central or peripheral nervous system (for exampleastrocytomas (e.g. gliomas), neuromas and glioblastomas, meningiomas,ependymomas, pineal tumours and schwannomas); endocrine tumours (forexample pituitary tumours, adrenal tumours, islet cell tumours,parathyroid tumours, carcinoid tumours and medullary carcinoma of thethyroid); ocular and adnexal tumours (for example retinoblastoma); germcell and trophoblastic tumours (for example teratomas, seminomas,dysgerminomas, hydatidiform moles and choriocarcinomas); and paediatricand embryonal tumours (for example medulloblastoma, neuroblastoma, Wilmstumour, and primitive neuroectodermal tumours); or syndromes, congenitalor otherwise, which leave the patient susceptible to malignancy (forexample Xeroderma Pigmentosum).

Growth of cells is a closely controlled function. Cancer, a condition ofabnormal cell growth, results when cells replicate in an uncontrolledmanner (increasing in number), uncontrollably grow (getting larger)and/or experience reduced cell death by apoptosis (programmed celldeath), necrosis, or annoikis. In one embodiment abnormal cell growth isselected from uncontrolled cell proliferation, excessive cell growth orreduced programmed cell death. In particular, the condition or diseaseof abnormal cell growth is a cancer.

Thus, in the pharmaceutical compositions, uses or methods of thisinvention for treating a disease or condition comprising abnormal cellgrowth (i.e. uncontrolled and/or rapid cell growth), the disease orcondition comprising abnormal cell growth in one embodiment is a cancer.

Many diseases are characterized by persistent and unregulatedangiogenesis. Chronic proliferative diseases are often accompanied byprofound angiogenesis, which can contribute to or maintain aninflammatory and/or proliferative state, or which leads to tissuedestruction through the invasive proliferation of blood vessels. Tumourgrowth and metastasis have been found to be angiogenesis-dependent.Compounds of the invention may therefore be useful in preventing anddisrupting initiation of tumour angiogenesis.

Angiogenesis is generally used to describe the development of new orreplacement blood vessels, or neovascularisation. It is a necessary andphysiological normal process by which vasculature is established in theembryo. Angiogenesis does not occur, in general, in most normal adulttissues, exceptions being sites of ovulation, menses and wound healing.Many diseases, however, are characterized by persistent and unregulatedangiogenesis. For instance, in arthritis, new capillary blood vesselsinvade the joint and destroy cartilage. In diabetes (and in manydifferent eye diseases), new vessels invade the macula or retina orother ocular structures, and may cause blindness. The process ofatherosclerosis has been linked to angiogenesis. Tumor growth andmetastasis have been found to be angiogenesis-dependent. The compoundsmay be beneficial in the treatment of diseases such as cancer andmetastasis, ocular diseases, arthritis and hemangioma.

Therefore, the compounds of the invention may be useful in the treatmentof metastasis and metastatic cancers. Metastasis or metastatic diseaseis the spread of a disease from one organ or part to anothernon-adjacent organ or part. The cancers which can be treated by thecompounds of the invention include primary tumours (i.e. cancer cells atthe originating site), local invasion (cancer cells which penetrate andinfiltrate surrounding normal tissues in the local area), and metastatic(or secondary) tumours ie. tumours that have formed from malignant cellswhich have circulated through the bloodstream (haematogenous spread) orvia lymphatics or across body cavities (trans-coelomic) to other sitesand tissues in the body. In particular, the compounds of the inventionmay be useful in the treatment of metastasis and metastatic cancers.

In one embodiment the haematological malignancies is a leukaemia. Inanother embodiment the haematological malignancies is a lymphoma. In oneembodiment the cancer is AML. In another embodiment the cancer is CLL.

In one embodiment the compound of the invention is for use in theprophylaxis or treatment of leukemia, such as acute or chronicleukaemia, in particular acute myeloid leukaemia (AML), acutelymphocytic leukaemia (ALL), chronic lymphocytic leukaemia (CLL), orchronic myeloid leukemia (CML). In one embodiment the compound of theinvention is for use in the prophylaxis or treatment of lymphoma, suchas acute or chronic lymphoma, in particular Burkitt lymphoma, Hodgkinlymphoma, non-Hodgkin lymphoma or diffuse large B-cell lymphoma.

In one embodiment the compound of the invention is for use in theprophylaxis or treatment of acute myeloid leukaemia (AML) or acutelymphocytic leukaemia (ALL).

One embodiment includes a compound of the invention for use in theprophylaxis or treatment of cancer in a patient selected from asub-population possessing cancers which are p53 wild-type or have anMDM2 amplification

The cancers may be cancers which are sensitive to treatment with MDM2inhibitors. The cancers may be cancers which overexpress MDM2. Thecancer may be cancers which are p53 wild-type.

Particular cancers include those with an MDM2 amplification and/or MDM2overexpression, for example, hepatocellular carcinoma, lung, sarcomas,osteosarcomas, and Hodgkin disease.

Particular cancers include those with wild-type p53. Particulars cancersinclude those cancer cells with wild-type p53, particularly but notexclusively, if MDM2 is highly expressed.

In one embodiment the cancer is a p53 functional tumours. In oneembodiment this disease to be treated is p53 functional solid andhaematological malignancies. In another embodiment the patient to betreated has p53 mutant tumour for example AML patients with p53 mutanttumour.

In one embodiment the cancer is a tumour of the brain, for exampleglioma, or neuroblastoma.

In one embodiment the cancer is a cancer of the skin, for examplemelanoma.

In one embodiment the cancer is a cancer of the lung, for examplemesothelioma. In one embodiment the mesothelioma is malignant peritonealmesothelioma or malignant pleural mesothelioma.

In one embodiment the cancer is a cancer of the gastrointestinal tract,for example GIST, gastric, colorectal or bowel.

In one embodiment the cancer is osteosarcoma.

In one embodiment the cancer is liposarcoma.

In one embodiment the cancer is Ewing's sarcoma.

In one embodiment, the cancer is liposarcoma, soft tissue sarcoma,osteosarcoma, oesophageal cancer, and certain paediatric malignanciesincluding B-cell malignancies.

In one embodiment, the cancer is colorectal, breast, lung and brain

In one embodiment, the cancer is a paediatric cancer.

Whether a particular cancer is one which is sensitive to MDM2inhibitors, may be determined by a method as set out in the sectionheaded “Methods of Diagnosis”.

A further aspect provides the use of a compound for the manufacture of amedicament for the treatment of a disease or condition as describedherein, in particular cancer.

Certain cancers are resistant to treatment with particular drugs. Thiscan be due to the type of the tumour (most common epithelialmalignancies are inherently chemoresistant and prostate is relativelyresistant to currently available regimens of chemotherapy or radiationtherapy) or resistance can arise spontaneously as the disease progressesor as a result of treatment. In this regard, references to prostateincludes prostate with resistance towards anti-androgen therapy, inparticular abiraterone or enzalutamide, or castrate-resistant prostate.Similarly references to multiple myeloma includes bortezomib-insensitivemultiple myeloma or refractory multiple myeloma and references tochronic myelogenous leukemia includes imitanib-insensitive chronicmyelogenous leukemia and refractory chronic myelogenous leukemia. Inthis regard, references to mesothelioma includes mesothelioma withresistance towards topoisomerase poisons, alkylating agents,antitubulines, antifolates, platinum compounds and radiation therapy, inparticular cisplatin-resistant mesothelioma.

The compounds may also be useful in the treatment of tumour growth,pathogenesis, resistance to chemo- and radio-therapy by sensitisingcells to chemotherapy and as an anti-metastatic agent.

Therapeutic anticancer interventions of all types necessarily increasethe stresses imposed on the target tumour cells. Inhibitors of MDM2/p53represent a class of chemotherapeutics with the potential for: (i)sensitizing malignant cells to anticancer drugs and/or treatments; (ii)alleviating or reducing the incidence of resistance to anticancer drugsand/or treatments; (iii) reversing resistance to anticancer drugs and/ortreatments; (iv) potentiating the activity of anticancer drugs and/ortreatments; (v) delaying or preventing the onset of resistance toanticancer drugs and/or treatments.

In one embodiment the invention provides a compound for use in thetreatment of a disease or condition which is mediated by MDM2. In afurther embodiment the disease or condition which is mediated by MDM2 isa cancer which is characterised by overexpression and/or increasedactivity of MDM2, or high copy number MDM2 and/or wildtype p53.

A further aspect provides the use of a compound for the manufacture of amedicament for the treatment of a disease or condition as describedherein, in particular cancer.

In one embodiment there is provided a compound for use in theprophylaxis or treatment of a disease or condition mediated by MDM2/p53.In one embodiment there is provided a compound for inhibiting theinteraction between of MDM2 protein with p53.

In one embodiment there is provided a pharmaceutical compositioncomprising an effective amount of at least one compound as defined. In afurther aspect of the present invention, there is provided a compound asdefined in the present

In one embodiment there is provided a method for the prophylaxis ortreatment of cancer comprising the steps of administering to a mammal amedicament comprising at least one compound as defined.

Methods of Diagnosis

Prior to administration of a compound of the formula (I), a patient maybe screened to determine whether a disease or condition from which thepatient is or may be suffering is one which would be susceptible totreatment with a compound which inhibits Mdm2/p53. The term ‘patient’includes human and veterinary subjects such as primates, in particularhuman patients.

For example, a biological sample taken from a patient may be analysed todetermine whether a condition or disease, such as cancer, that thepatient is or may be suffering from is one which is characterised by agenetic abnormality or abnormal protein expression which leads toup-regulation of the levels of MDM2 or to upregulation of a biochemicalpathway downstream of MDM2/p53.

Examples of such abnormalities that result in activation orsensitisation of MDM2, loss of, or inhibition of regulatory pathwaysimpacting on MDM2 expression, up-regulation of receptors or theirligands, cytogenetic aberrations or presence of mutant variants of thereceptors or ligands. Tumours with up-regulation of MDM2/p53, inparticular over-expression of MDM2 or exhibit wild-type p53, may beparticularly sensitive to inhibitors of MDM2/p53. For example,amplification of MDM2 and/or deletion of its negative regulator such asp14ARF has been identified in a range of cancers as discussion in theIntroduction section.

The term up-regulation includes elevated expression or over-expression,including gene amplification (i.e. multiple gene copies), cytogeneticaberration and increased expression by a transcriptional orpost-translational effect. Thus, the patient may be subjected to adiagnostic test to detect a marker characteristic of up-regulation ofMDM2. The term diagnosis includes screening. By marker we includegenetic markers including, for example, the measurement of DNAcomposition to identify presence of mutations in p53 or amplificationMDM2 or deletion (loss) of p14ARF. The term marker also includes markerswhich are characteristic of up regulation of MDM2/p53, including proteinlevels, protein state and mRNA levels of the aforementioned proteins.Gene amplification includes greater than 7 copies, as well as gains ofbetween 2 and 7 copies.

The diagnostic tests and screens are typically conducted on a biologicalsample (i.e. body tissue or body fluids) selected from tumour biopsysamples, blood samples (isolation and enrichment of shed tumour cells),cerebrospinal fluid, plasma, serum, saliva, stool biopsies, sputum,chromosome analysis, pleural fluid, peritoneal fluid, buccal smears,skin biopsy or urine.

Methods of identification and analysis of cytogenetic aberration,genetic amplification, mutations and up-regulation of proteins are knownto a person skilled in the art. Screening methods could include, but arenot limited to, standard methods such as DNA sequence analysis byconventional Sanger or next-generation sequencing methods,reverse-transcriptase polymerase chain reaction (RT-PCR), RNA sequencing(RNAseq), nanostring hybridisation proximity RNA nCounter assays, orin-situ hybridization such as fluorescence in situ hybridization (FISH)or allele-specific polymerase chain reaction (PCR).

In screening by RT-PCR, the level of mRNA in the tumour is assessed bycreating a cDNA copy of the mRNA followed by amplification of the cDNAby PCR. Methods of PCR amplification, the selection of primers, andconditions for amplification, are known to a person skilled in the art.Nucleic acid manipulations and PCR are carried out by standard methods,as described for example in Ausubel, F. M. et al., eds. (2004) CurrentProtocols in Molecular Biology, John Wiley & Sons Inc., or Innis, M. A.et al., eds. (1990) PCR Protocols: a guide to methods and applications,Academic Press, San Diego. Reactions and manipulations involving nucleicacid techniques are also described in Sambrook et al., (2001), 3^(rd)Ed, Molecular Cloning: A Laboratory Manual, Cold Spring HarborLaboratory Press. Alternatively a commercially available kit for RT-PCR(for example Roche Molecular Biochemicals) may be used, or methodologyas set forth in U.S. Pat. Nos. 4,666,828; 4,683,202; 4,801,531;5,192,659, 5,272,057, 5,882,864, and 6,218,529 and incorporated hereinby reference. An example of an in-situ hybridisation technique forassessing mRNA expression would be fluorescence in-situ hybridisation(FISH) (see Angerer (1987) Meth. Enzymol., 152: 649).

Generally, in situ hybridization comprises the following major steps:(1) fixation of tissue to be analyzed; (2) prehybridization treatment ofthe sample to increase accessibility of target nucleic acid, and toreduce nonspecific binding; (3) hybridization of the mixture of nucleicacids to the nucleic acid in the biological structure or tissue; (4)post-hybridization washes to remove nucleic acid fragments not bound inthe hybridization, and (5) detection of the hybridized nucleic acidfragments. The probes used in such applications are typically labelled,for example, with radioisotopes or fluorescent reporters. Certain probesare sufficiently long, for example, from about 50, 100, or 200nucleotides to about 1000 or more nucleotides, to enable specifichybridization with the target nucleic acid(s) under stringentconditions. Standard methods for carrying out FISH are described inAusubel, F. M. et al., eds. (2004) Current Protocols in MolecularBiology, John Wiley & Sons Inc and Fluorescence In Situ Hybridization:Technical Overview by John M. S. Bartlett in Molecular Diagnosis ofCancer, Methods and Protocols, 2nd ed.; ISBN: 1-59259-760-2; March 2004,pps. 077-088; Series: Methods in Molecular Medicine.

Methods for gene expression profiling are described by (DePrimo et al.(2003), BMC Cancer, 3:3). Briefly, the protocol is as follows:double-stranded cDNA is synthesized from total RNA using a (dT)24oligomer for priming first-strand cDNA synthesis from polyadenylatedmRNA, followed by second strand cDNA synthesis with random hexamerprimers. The double-stranded cDNA is used as a template for in vitrotranscription of cRNA using biotinylated ribonucleotides. cRNA ischemically fragmented according to protocols described by Affymetrix(Santa Clara, Calif., USA), and then hybridized overnight togene-specific oligonucleotide probes on Human Genome Arrays.Alternatively, single nucleotide polymorphism (SNP) arrays, a type ofDNA microarray, can be used to detect polymorphisms within a population.

Alternatively, the protein products expressed from the mRNAs may beassayed by immunohistochemistry of tumour samples, solid phaseimmunoassay with microtitre plates, Western blotting, 2-dimensionalSDS-polyacrylamide gel electrophoresis, ELISA, flow cytometry and othermethods known in the art for detection of specific proteins e.g.capillary electrophoresis. Detection methods would include the use ofsite specific antibodies. The skilled person will recognize that allsuch well-known techniques can be used for detection of upregulation ofMDM2 and p53, detection of MDM2 or p53 variants or mutants, or loss ofnegative regulators of MDM2 in the present case.

Abnormal levels of proteins such as MDM2 or p53 can be measured usingstandard protein assays, for example, those assays described herein.Elevated levels or overexpression could also be detected in a tissuesample, for example, a tumour tissue by measuring the protein levelswith an assay such as that from Chemicon International. The protein ofinterest would be immunoprecipitated from the sample lysate and itslevels measured. Assay methods also include the use of markers.

In other words, p53 and MDM2 overexpression can be measured by tumourbiopsy.

Methods for assessing gene copy changes include techniques commonly usedin cytogenetic laboratories such as MLPA (Multiplex Ligation-dependentProbe Amplification) a multiplex PCR method detecting abnormal copynumbers, or other PCR techniques which can detect gene amplification,gain and deletion.

Ex-functional assays could also be utilised where appropriate, forexample measurement of circulating leukemia cells in a cancer patient,to assess the response to challenge with an MDM2/p53 inhibitor.

Therefore all of these techniques could also be used to identify tumoursparticularly suitable for treatment with the compounds of the invention.

Therefore in a further aspect of the invention includes use of acompound according to the invention for the manufacture of a medicamentfor the treatment or prophylaxis of a disease state or condition in apatient who has been screened and has been determined as suffering from,or being at risk of suffering from, a disease or condition which wouldbe susceptible to treatment with an MDM2/p53 inhibitor.

Another aspect of the invention includes a compound of the invention foruse in the prophylaxis or treatment of cancer in a patient selected froma sub-population possessing amplification of MDM2.

Another aspect of the invention includes a compound of the invention foruse in the prophylaxis or treatment of cancer in a patient selected froma sub-population possessing p53 wild-type.

Another aspect of the invention includes a compound of the invention foruse in the prophylaxis or treatment of cancer in a patient possessingloss of a MDM2 negative regulator such as p14ARF.

MRI determination of vessel normalization (e.g. using MRI gradient echo,spin echo, and contrast enhancement to measure blood volume, relativevessel size, and vascular permeability) in combination with circulatingbiomarkers may also be used to identify patients suitable for treatmentwith a compound of the invention.

Thus a further aspect of the invention is a method for the diagnosis andtreatment of a disease state or condition mediated by MDM2/p53, whichmethod comprises (i) screening a patient to determine whether a diseaseor condition from which the patient is or may be suffering is one whichwould be susceptible to treatment with MDM2/p53 inhibitor; and (ii)where it is indicated that the disease or condition from which thepatient is thus susceptible, thereafter administering to the patient acompound of formula (I) and sub-groups or examples thereof as definedherein.

Advantages of Compounds of the Invention

The compounds of the formula (I) have a number of advantages over priorart compounds.

Compounds of the invention may have particular advantage in one or moreof the following aspects:

-   -   (i) Superior potency;    -   (ii) Superior in vivo efficacy    -   (iii) Superior PK;    -   (iv) Superior metabolic stability;    -   (v) Superior oral bioavailability; and    -   (vi) Superior physiochemical properties.

Superior Potency and In Vivo Efficacy

The compounds of the formula (I) have increased affinity for MDM2 and inparticular increased cell potency against cell lines known to besensitive to MDM2 antagonists.

Enhanced target engagement is a highly desirable property in apharmaceutical compound as it allows for a reduced dosage of drug and agood separation (‘therapeutic window’) between MDM2 activity and toxiceffects.

The compounds of the formula (I) have improved cell potency and/orimproved selectivity for p53 WT vs mutant p53 cell lines. As a result ofincreased potency against MDM2 compounds of the invention may haveincreased in vivo efficacy in cancer cell lines and in vivo models. Inaddition the compounds show selectivity for MDM2 over MDMX, despite theclose sequence, structural and functional similarity between thesegenetic paralogues.

Superior PK and Metabolic Stability

The compounds of the formula (I) may have advantageous ADMET propertiesfor example better metabolic stability (for example as determined withmouse liver microsomes), a better P450 profile, short half-life and/orbeneficial clearance (e.g. low or high clearance). It has also beenfound that many compounds of the formula (I) have an improved PKprofile.

These features could confer the advantage of having more drug availablein the systemic circulation to reach the appropriate site of action toexert its therapeutic effect. Increased drug concentrations to exertpharmacological action in tumours potentially leads to improved efficacywhich thereby allows reduced dosages to be administered. Thus, thecompounds of formula (I) should exhibit reduced dosage requirements andshould be more readily formulated and administered.

This results in a good separation (‘therapeutic window’) between MDM2activity and toxic effects.

Many compounds of the formula (I) have a reduction in Cmax required forefficacy (due to better MDM2 potency and/or PK).

Superior Oral Bioavailability

Potentially the compounds of the invention have physiochemicalproperties suitable for oral exposure (oral exposure or AUC). Inparticular, compounds of the formula (I) may exhibit improved oralbioavailability or improved reproducibility of oral absorption. Oralbioavailability can be defined as the ratio (F) of the plasma exposureof a compound when dosed by the oral route to the plasma exposure of thecompound when dosed by the intravenous (i.v.) route, expressed as apercentage.

Compounds having an oral bioavailability (F value) of greater than 10%,20% or 30%, more particularly greater than 40%, are particularlyadvantageous in that they may be administered orally rather than, or aswell as, by parenteral administration.

Superior Physiochemical Properties

The compounds of the formula (I) may have advantageous physiochemicalproperties in particular chemical stability in acidic conditions andreduced lipophilicity.

Lipophilicity can be measured using a partition-coefficient (log P) or adistribution-coefficient (log D). The partition coefficient is a ratioof concentrations of un-ionized compound between two immiscible phases(n-octanol and water) at equilibrium whereas the distributioncoefficient is the ratio of the sum of the concentrations of all formsof the compound (ionized plus un-ionized) in each of the two phases.High lipophilicity is associated with poor drug like properties such uslow aqueous solubility, poor pharmacokinetics properties (low oralbioavailability), undesired drug metabolism and high promiscuity.Compounds with optimal lipophilicity might have greater chances ofsuccess in drug development. However reduced log P (or calculated log P,clogP) can be challenging to achieve whilst retaining an acceptablelevel of potency for inhibition of protein-protein interactions (PPIs)due to the lipophilic nature of the targets involved.

Pharmaceutical Formulations

While it is possible for the active compound to be administered alone,it is generally presented as a pharmaceutical composition (e.g.formulation).

Thus, the present invention further provides pharmaceuticalcompositions, as defined above, and methods of making a pharmaceuticalcomposition comprising (e.g admixing) at least one compound of formula(I) (and sub-groups thereof as defined herein), together with one ormore pharmaceutically acceptable excipients and optionally othertherapeutic or prophylactic agents as described herein.

The pharmaceutically acceptable excipient(s) can be selected from, forexample, carriers (e.g. a solid, liquid or semi-solid carrier),adjuvants, diluents, fillers or bulking agents, granulating agents,coating agents, release-controlling agents, binding agents,disintegrants, lubricating agents, preservatives, antioxidants,buffering agents, suspending agents, thickening agents, flavouringagents, sweeteners, taste masking agents, stabilisers or any otherexcipients conventionally used in pharmaceutical compositions. Examplesof excipients for various types of pharmaceutical compositions are setout in more detail below.

The term “pharmaceutically acceptable” as used herein pertains tocompounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of a subject (e.g. a human subject) without excessivetoxicity, irritation, allergic response, or other problem orcomplication, commensurate with a reasonable benefit/risk ratio. Eachexcipient must also be “acceptable” in the sense of being compatiblewith the other ingredients of the formulation.

Pharmaceutical compositions containing compounds of the formula (I) canbe formulated in accordance with known techniques, see for example,Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton,Pa., USA.

The pharmaceutical compositions can be in any form suitable for oral,parenteral, topical, intranasal, intrabronchial, sublingual, ophthalmic,otic, rectal, intra-vaginal, or transdermal administration. Where thecompositions are intended for parenteral administration, they can beformulated for intravenous, intramuscular, intraperitoneal, subcutaneousadministration or for direct delivery into a target organ or tissue byinjection, infusion or other means of delivery. The delivery can be bybolus injection, short-term infusion or longer term infusion and can bevia passive delivery or through the utilisation of a suitable infusionpump or syringe driver.

Pharmaceutical formulations adapted for parenteral administrationinclude aqueous and non-aqueous sterile injection solutions which maycontain anti-oxidants, buffers, bacteriostats, co-solvents, surfaceactive agents, organic solvent mixtures, cyclodextrin complexationagents, emulsifying agents (for forming and stabilizing emulsionformulations), liposome components for forming liposomes, gellablepolymers for forming polymeric gels, lyophilisation protectants andcombinations of agents for, inter alia, stabilising the activeingredient in a soluble form and rendering the formulation isotonic withthe blood of the intended recipient. Pharmaceutical formulations forparenteral administration may also take the form of aqueous andnon-aqueous sterile suspensions which may include suspending agents andthickening agents (R. G. Strickly, Solubilizing Excipients in oral andinjectable formulations, Pharmaceutical Research, Vol 21(2) 2004, p201-230).

The formulations may be presented in unit-dose or multi-dose containers,for example sealed ampoules, vials and prefilled syringes, and may bestored in a freeze-dried (lyophilised) condition requiring only theaddition of the sterile liquid carrier, for example water forinjections, immediately prior to use. In one embodiment, the formulationis provided as an active pharmaceutical ingredient in a bottle forsubsequent reconstitution using an appropriate diluent.

The pharmaceutical formulation can be prepared by lyophilising acompound of formula (I), or sub-groups thereof. Lyophilisation refers tothe procedure of freeze-drying a composition. Freeze-drying andlyophilisation are therefore used herein as synonyms.

Extemporaneous injection solutions and suspensions may be prepared fromsterile powders, granules and tablets.

Pharmaceutical compositions of the present invention for parenteralinjection can also comprise pharmaceutically acceptable sterile aqueousor non-aqueous solutions, dispersions, suspensions or emulsions as wellas sterile powders for reconstitution into sterile injectable solutionsor dispersions just prior to use. Examples of suitable aqueous andnonaqueous carriers, diluents, solvents or vehicles include water,ethanol, polyols (such as glycerol, propylene glycol, polyethyleneglycol, and the like), carboxymethylcellulose and suitable mixturesthereof, vegetable oils (such as sunflower oil, safflower oil, corn oilor olive oil), and injectable organic esters such as ethyl oleate.Proper fluidity can be maintained, for example, by the use of thickeningmaterials such as lecithin, by the maintenance of the required particlesize in the case of dispersions, and by the use of surfactants.

The compositions of the present invention may also contain adjuvantssuch as preservatives, wetting agents, emulsifying agents, anddispersing agents. Prevention of the action of microorganisms may beensured by the inclusion of various antibacterial and antifungal agents,for example, paraben, chlorobutanol, phenol, sorbic acid, and the like.It may also be desirable to include agents to adjust tonicity such assugars, sodium chloride, and the like. Prolonged absorption of theinjectable pharmaceutical form may be brought about by the inclusion ofagents which delay absorption such as aluminum monostearate and gelatin.

In one typical embodiment of the invention, the pharmaceuticalcomposition is in a form suitable for i.v. administration, for exampleby injection or infusion. For intravenous administration, the solutioncan be dosed as is, or can be injected into an infusion bag (containinga pharmaceutically acceptable excipient, such as 0.9% saline or 5%dextrose), before administration.

In another typical embodiment, the pharmaceutical composition is in aform suitable for sub-cutaneous (s.c.) administration.

Pharmaceutical dosage forms suitable for oral administration includetablets (coated or uncoated), capsules (hard or soft shell), caplets,pills, lozenges, syrups, solutions, powders, granules, elixirs andsuspensions, sublingual tablets, wafers or patches such as buccalpatches.

Thus, tablet compositions can contain a unit dosage of active compoundtogether with an inert diluent or carrier such as a sugar or sugaralcohol, eg; lactose, sucrose, sorbitol or mannitol; and/or a non-sugarderived diluent such as sodium carbonate, calcium phosphate, calciumcarbonate, or a cellulose or derivative thereof such as microcrystallinecellulose (MCC), methyl cellulose, ethyl cellulose, hydroxypropyl methylcellulose, and starches such as corn starch. Tablets may also containsuch standard ingredients as binding and granulating agents such aspolyvinylpyrrolidone, disintegrants (e.g. swellable crosslinked polymerssuch as crosslinked carboxymethylcellulose), lubricating agents (e.g.stearates), preservatives (e.g. parabens), antioxidants (e.g. BHT),buffering agents (for example phosphate or citrate buffers), andeffervescent agents such as citrate/bicarbonate mixtures. Suchexcipients are well known and do not need to be discussed in detailhere.

Tablets may be designed to release the drug either upon contact withstomach fluids (immediate release tablets) or to release in a controlledmanner (controlled release tablets) over a prolonged period of time orwith a specific region of the GI tract.

Capsule formulations may be of the hard gelatin or soft gelatin varietyand can contain the active component in solid, semi-solid, or liquidform. Gelatin capsules can be formed from animal gelatin or synthetic orplant derived equivalents thereof.

The solid dosage forms (eg; tablets, capsules etc.) can be coated orun-coated. Coatings may act either as a protective film (e.g. a polymer,wax or varnish) or as a mechanism for controlling drug release or foraesthetic or identification purposes. The coating (e.g. a Eudragit™ typepolymer) can be designed to release the active component at a desiredlocation within the gastro-intestinal tract. Thus, the coating can beselected so as to degrade under certain pH conditions within thegastrointestinal tract, thereby selectively release the compound in thestomach or in the ileum, duodenum, jejenum or colon.

Instead of, or in addition to, a coating, the drug can be presented in asolid matrix comprising a release controlling agent, for example arelease delaying agent which may be adapted to release the compound in acontrolled manner in the gastrointestinal tract. Alternatively the drugcan be presented in a polymer coating e.g. a polymethacrylate polymercoating, which may be adapted to selectively release the compound underconditions of varying acidity or alkalinity in the gastrointestinaltract. Alternatively, the matrix material or release retarding coatingcan take the form of an erodible polymer (e.g. a maleic anhydridepolymer) which is substantially continuously eroded as the dosage formpasses through the gastrointestinal tract. In another alternative, thecoating can be designed to disintegrate under microbial action in thegut. As a further alternative, the active compound can be formulated ina delivery system that provides osmotic control of the release of thecompound. Osmotic release and other delayed release or sustained releaseformulations (for example formulations based on ion exchange resins) maybe prepared in accordance with methods well known to those skilled inthe art.

The compound of formula (I) may be formulated with a carrier andadministered in the form of nanoparticles, the increased surface area ofthe nanoparticles assisting their absorption. In addition, nanoparticlesoffer the possibility of direct penetration into the cell. Nanoparticledrug delivery systems are described in “Nanoparticle Technology for DrugDelivery”, edited by Ram B Gupta and Uday B. Kompella, InformaHealthcare, ISBN 9781574448573, published 13 Mar. 2006. Nanoparticlesfor drug delivery are also described in J. Control. Release, 2003, 91(1-2), 167-172, and in Sinha et al., Mol. Cancer Ther. August 1, (2006)5, 1909.

The pharmaceutical compositions typically comprise from approximately 1%(w/w) to approximately 95% active ingredient and from 99% (w/w) to 5%(w/w) of a pharmaceutically acceptable excipient or combination ofexcipients. Typically, the compositions comprise from approximately 20%(w/w) to approximately 90%,% (w/w) active ingredient and from 80% (w/w)to 10% of a pharmaceutically acceptable excipient or combination ofexcipients. The pharmaceutical compositions comprise from approximately1% to approximately 95%, typically from approximately 20% toapproximately 90%, active ingredient. Pharmaceutical compositionsaccording to the invention may be, for example, in unit dose form, suchas in the form of ampoules, vials, suppositories, pre-filled syringes,dragées, tablets or capsules.

The pharmaceutically acceptable excipient(s) can be selected accordingto the desired physical form of the formulation and can, for example, beselected from diluents (e.g solid diluents such as fillers or bulkingagents; and liquid diluents such as solvents and co-solvents),disintegrants, buffering agents, lubricants, flow aids, releasecontrolling (e.g. release retarding or delaying polymers or waxes)agents, binders, granulating agents, pigments, plasticizers,antioxidants, preservatives, flavouring agents, taste masking agents,tonicity adjusting agents and coating agents.

The skilled person will have the expertise to select the appropriateamounts of ingredients for use in the formulations. For example tabletsand capsules typically contain 0-20% disintegrants, 0-5% lubricants,0-5% flow aids and/or 0-99% (w/w) fillers/or bulking agents (dependingon drug dose).

They may also contain 0-10% (w/w) polymer binders, 0-5% (w/w)antioxidants, 0-5% (w/w) pigments. Slow release tablets would inaddition contain 0-99% (w/w) polymers (depending on dose). The filmcoats of the tablet or capsule typically contain 0-10% (w/w)release-controlling (e.g. delaying) polymers, 0-3% (w/w) pigments,and/or 0-2% (w/w) plasticizers.

Parenteral formulations typically contain 0-20% (w/w) buffers, 0-50%(w/w) cosolvents, and/or 0-99% (w/w) Water for Injection (WFI)(depending on dose and if freeze dried). Formulations for intramusculardepots may also contain 0-99% (w/w) oils.

Pharmaceutical compositions for oral administration can be obtained bycombining the active ingredient with solid carriers, if desiredgranulating a resulting mixture, and processing the mixture, if desiredor necessary, after the addition of appropriate excipients, intotablets, dragee cores or capsules. It is also possible for them to beincorporated into a polymer or waxy matrix that allow the activeingredients to diffuse or be released in measured amounts.

The compounds of the invention can also be formulated as soliddispersions. Solid dispersions are homogeneous extremely fine dispersephases of two or more solids. Solid solutions (molecularly dispersesystems), one type of solid dispersion, are well known for use inpharmaceutical technology (see (Chiou and Riegelman, J. Pharm. Sci., 60,1281-1300 (1971)) and are useful in increasing dissolution rates andincreasing the bioavailability of poorly water-soluble drugs.

This invention also provides solid dosage forms comprising the solidsolution described herein. Solid dosage forms include tablets, capsules,chewable tablets and dispersible or effervescent tablets. Knownexcipients can be blended with the solid solution to provide the desireddosage form. For example, a capsule can contain the solid solutionblended with (a) a disintegrant and a lubricant, or (b) a disintegrant,a lubricant and a surfactant. In addition a capsule can contain abulking agent, such as lactose or microcrystalline cellulose. A tabletcan contain the solid solution blended with at least one disintegrant, alubricant, a surfactant, a bulking agent and a glidant. A chewabletablet can contain the solid solution blended with a bulking agent, alubricant, and if desired an additional sweetening agent (such as anartificial sweetener), and suitable flavours. Solid solutions may alsobe formed by spraying solutions of drug and a suitable polymer onto thesurface of inert carriers such as sugar beads (‘non-pareils’). Thesebeads can subsequently be filled into capsules or compressed intotablets.

The pharmaceutical formulations may be presented to a patient in“patient packs” containing an entire course of treatment in a singlepackage, usually a blister pack. Patient packs have an advantage overtraditional prescriptions, where a pharmacist divides a patient's supplyof a pharmaceutical from a bulk supply, in that the patient always hasaccess to the package insert contained in the patient pack, normallymissing in patient prescriptions. The inclusion of a package insert hasbeen shown to improve patient compliance with the physician'sinstructions.

Compositions for topical use and nasal delivery include ointments,creams, sprays, patches, gels, liquid drops and inserts (for exampleintraocular inserts). Such compositions can be formulated in accordancewith known methods.

Examples of formulations for rectal or intra-vaginal administrationinclude pessaries and suppositories which may be, for example, formedfrom a shaped moldable or waxy material containing the active compound.Solutions of the active compound may also be used for rectaladministration.

Compositions for administration by inhalation may take the form ofinhalable powder compositions or liquid or powder sprays, and can beadministrated in standard form using powder inhaler devices or aerosoldispensing devices. Such devices are well known. For administration byinhalation, the powdered formulations typically comprise the activecompound together with an inert solid powdered diluent such as lactose.

The compounds of the formula (I) will generally be presented in unitdosage form and, as such, will typically contain sufficient compound toprovide a desired level of biological activity. For example, aformulation may contain from 1 nanogram to 2 grams of active ingredient,e.g. from 1 nanogram to 2 milligrams of active ingredient. Within theseranges, particular sub-ranges of compound are 0.1 milligrams to 2 gramsof active ingredient (more usually from 10 milligrams to 1 gram, e.g. 50milligrams to 500 milligrams), or 1 microgram to 20 milligrams (forexample 1 microgram to 10 milligrams, e.g. 0.1 milligrams to 2milligrams of active ingredient).

For oral compositions, a unit dosage form may contain from 1 milligramto 2 grams, more typically 10 milligrams to 1 gram, for example 50milligrams to 1 gram, e.g. 100 milligrams to 1 gram, of active compound.

The active compound will be administered to a patient in need thereof(for example a human or animal patient) in an amount sufficient toachieve the desired therapeutic effect.

Methods of Treatment

The compounds of the formula (I) and sub-groups as defined herein may beuseful in the prophylaxis or treatment of a range of disease states orconditions mediated by MDM2/p53. Examples of such disease states andconditions are set out above.

The compounds are generally administered to a subject in need of suchadministration, for example a human or animal patient, typically ahuman.

The compounds will typically be administered in amounts that aretherapeutically or prophylactically useful and which generally arenon-toxic. However, in certain situations (for example in the case oflife threatening diseases), the benefits of administering a compound ofthe formula (I) may outweigh the disadvantages of any toxic effects orside effects, in which case it may be considered desirable to administercompounds in amounts that are associated with a degree of toxicity.

The compounds may be administered over a prolonged term to maintainbeneficial therapeutic effects or may be administered for a short periodonly. Alternatively they may be administered in a continuous manner orin a manner that provides intermittent dosing (e.g. a pulsatile manner).

A typical daily dose of the compound of formula (I) can be in the rangefrom 100 picograms to 100 milligrams per kilogram of body weight, moretypically 5 nanograms to 25 milligrams per kilogram of bodyweight, andmore usually 10 nanograms to 15 milligrams per kilogram (e.g. 10nanograms to 10 milligrams, and more typically 1 microgram per kilogramto 20 milligrams per kilogram, for example 1 microgram to 10 milligramsper kilogram) per kilogram of bodyweight although higher or lower dosesmay be administered where required. The compound of the formula (I) canbe administered on a daily basis or on a repeat basis every 2, or 3, or4, or 5, or 6, or 7, or 10 or 14, or 21, or 28 days for example.

Dosages may also be expressed as the amount of drug administeredrelative to the body surface area of the patient (mg/m²). A typicaldaily dose of the compound of formula (I) can be in the range from 3700pg/m² to 3700 mg/m², more typically 185 ng/m² to 925 mg/m², and moreusually 370 ng/m² to 555 mg/m² (e.g. 370 ng/m² to 370 mg/m², and moretypically 37 mg/m² to 740 mg/m², for example 37 mg/m² to 370 mg/m²)although higher or lower doses may be administered where required. Thecompound of the formula (I) can be administered on a daily basis or on arepeat basis every 2, or 3, or 4, or 5, or 6, or 7, or 10 or 14, or 21,or 28 days for example.

The compounds of the invention may be administered orally in a range ofdoses, for example 0.1 to 5000 mg, or 1 to 1500 mg, 2 to 800 mg, or 5 to500 mg, e.g. 2 to 200 mg or 10 to 1000 mg, particular examples of dosesincluding 10, 20, 50 and 80 mg. The compound may be administered once ormore than once each day. The compound can be administered continuously(i.e. taken every day without a break for the duration of the treatmentregimen). Alternatively, the compound can be administered intermittently(i.e. taken continuously for a given period such as a week, thendiscontinued for a period such as a week and then taken continuously foranother period such as a week and so on throughout the duration of thetreatment regimen). Examples of treatment regimens involvingintermittent administration include regimens wherein administration isin cycles of one week on, one week off; or two weeks on, one week off;or three weeks on, one week off; or two weeks on, two weeks off; or fourweeks on two weeks off; or one week on three weeks off—for one or morecycles, e.g. 2, 3, 4, 5, 6, 7, 8, 9 or 10 or more cycles. Thisdiscontinuous treatment can also be based upon numbers of days ratherthan a full week. For example, the treatment can comprise daily dosingfor 1 to 6 days, no dosing for 1 to 6 days with this pattern repeatingduring the treatment protocol. The number of days (or weeks) wherein thecompounds of the invention are not dosed do not necessarily have toequal the number of days (or weeks) wherein the compounds of theinvention are dosed.

In one embodiment, the compounds of the invention can be administered inamounts from 3 mg/m² to 125 mg/m² daily. Treatment can be by continuousdaily dosing or more usually consist of multiple cycles of treatmentseparated by treatment breaks. One example of a single treatment cycleis 5 consecutive daily doses followed by 3 weeks without treatment.

One particular dosing regimen is once a day (e.g. orally) for a week(e.g. 5 days of treatment), followed by a treatment break of 1, 2, or 3weeks. An alternative dosing regimen is once a week (e.g. orally), for1, 2, 3 or 4 weeks.

In one particular dosing schedule, a patient will be given an infusionof a compound of the formula (I) for periods of one hour daily for up toten days in particular up to five days for one week, and the treatmentrepeated at a desired interval such as two to four weeks, in particularevery three weeks.

More particularly, a patient may be given an infusion of a compound ofthe formula (I) for periods of one hour daily for 5 days and thetreatment repeated every three weeks.

In another particular dosing schedule, a patient is given an infusionover 30 minutes to 1 hour followed by maintenance infusions of variableduration, for example 1 to 5 hours, e.g. 3 hours.

The compounds of the invention can also be administered by bolus orcontinuous infusion. The compound of the invention can be given daily toonce every week, or once every two weeks, or once every three weeks, oronce every four weeks during the treatment cycle. If administered dailyduring a treatment cycle, this daily dosing can be discontinuous overthe number of weeks of the treatment cycle: for example, dosed for aweek (or a number of days), no dosing for a week (or a number of days,with the pattern repeating during the treatment cycle.

In a further particular dosing schedule, a patient is given a continuousinfusion for a period of 12 hours to 5 days, and in particular acontinuous infusion of 24 hours to 72 hours.

Ultimately, however, the quantity of compound administered and the typeof composition used will be commensurate with the nature of the diseaseor physiological condition being treated and will be at the discretionof the physician.

It may be beneficial to use a compound of the invention as a singleagent or to combine the compound of the invention with another agentwhich acts via a different mechanism to regulate cell growth thustreating two of the characteristic features of cancer development.Combination experiments can be performed, for example, as described inChou T C, Talalay P. Quantitative analysis of dose-effect relationships:the combined effects of multiple drugs or enzyme inhibitors. Adv EnzymeRegulat 1984; 22: 27-55.

The compounds as defined herein can be administered as the soletherapeutic agent or they can be administered in combination therapywith one of more other compounds (or therapies) for treatment of aparticular disease state, for example a neoplastic disease such as acancer as hereinbefore defined.

For the treatment of the above conditions, the compounds of theinvention may be advantageously employed in combination with one or moreother medicinal agents, more particularly, with other anti-cancer agentsor adjuvants (supporting agents in the therapy) in cancer therapy.Examples of other therapeutic agents or treatments that may beadministered together (whether concurrently or at different timeintervals) with the compounds of the formula (I) include but are notlimited to:

-   -   Topoisomerase I inhibitors    -   Antimetabolites    -   Tubulin targeting agents    -   DNA binder and topoisomerase II inhibitors    -   Alkylating Agents    -   Monoclonal Antibodies.    -   Anti-Hormones    -   Signal Transduction Inhibitors    -   Proteasome Inhibitors    -   DNA methyl transferase inhibitors    -   Cytokines and retinoids    -   Chromatin targeted therapies    -   Radiotherapy, and,    -   Other therapeutic or prophylactic agents.

Particular examples of anti-cancer agents or adjuvants (or saltsthereof), include but are not limited to any of the agents selected fromgroups (i)-(xlviii), and optionally group (xlix), below:

-   (i) Platinum compounds, for example cisplatin (optionally combined    with amifostine), carboplatin or oxaliplatin;-   (ii) Taxane compounds, for example paclitaxel, paclitaxel protein    bound particles (Abraxane™), docetaxel, cabazitaxel or larotaxel;-   (iii) Topoisomerase I inhibitors, for example camptothecin    compounds, for example camptothecin, irinotecan(CPT11), SN-38, or    topotecan;-   (iv) Topoisomerase II inhibitors, for example anti-tumour    epipodophyllotoxins or podophyllotoxin derivatives for example    etoposide, or teniposide;-   (v) Vinca alkaloids, for example vinblastine, vincristine, liposomal    vincristine (Onco-TCS), vinorelbine, vindesine, vinflunine or    vinvesir;-   (vi) Nucleoside derivatives, for example 5-fluorouracil (5-FU,    optionally in combination with leucovorin), gemcitabine,    capecitabine, tegafur, UFT, S1, cladribine, cytarabine (Ara-C,    cytosine arabinoside), fludarabine, clofarabine, or nelarabine;-   (vii) Antimetabolites, for example clofarabine, aminopterin, or    methotrexate, azacitidine, cytarabine, floxuridine, pentostatin,    thioguanine, thiopurine, 6-mercaptopurine, or hydroxyurea    (hydroxycarbamide);-   (viii) Alkylating agents, such as nitrogen mustards or nitrosourea,    for example cyclophosphamide, chlorambucil, carmustine (BCNU),    bendamustine, thiotepa, melphalan, treosulfan, lomustine (CCNU),    altretamine, busulfan, dacarbazine, estramustine, fotemustine,    ifosfamide (optionally in combination with mesna), pipobroman,    procarbazine, streptozocin, temozolomide, uracil, mechlorethamine,    methylcyclohexylchloroethylnitrosurea, or nimustine (ACNU);-   (ix) Anthracyclines, anthracenediones and related drugs, for example    daunorubicin, doxorubicin (optionally in combination with    dexrazoxane), liposomal formulations of doxorubicin (eg. Caelyx™,    Myocet™, Doxil™), idarubicin, mitoxantrone, epirubicin, amsacrine,    or valrubicin;-   (x) Epothilones, for example ixabepilone, patupilone, BMS-310705,    KOS-862 and ZK-EPO, epothilone A, epothilone B, desoxyepothilone B    (also known as epothilone D or KOS-862), aza-epothilone B (also    known as BMS-247550), aulimalide, isolaulimalide, or luetherobin;-   (xi) DNA methyl transferase inhibitors, for example temozolomide,    azacytidine, or decitabine;-   (xii) Antifolates, for example methotrexate, pemetrexed disodium, or    raltitrexed;-   (xiii) Cytotoxic antibiotics, for example antinomycin D, bleomycin,    mitomycin C, dactinomycin, carminomycin, daunomycin, levamisole,    plicamycin, or mithramycin;-   (xiv) Tubulin-binding agents, for example combrestatin, colchicines    or nocodazole;-   (xv) Signal Transduction inhibitors such as Kinase inhibitors for    example receptor tyrosine kinase inhibitors (e.g. EGFR (epithelial    growth factor receptor) inhibitors, VEGFR (vascular endothelial    growth factor receptor) inhibitors, PDGFR (platelet-derived growth    factor receptor) inhibitors, Axl inhibitors, MTKI (multi target    kinase inhibitors), Raf inhibitors, ROCK inhibitors, mTOR    inhibitors, MEK inhibitors or PI3K Inhibitors) for example imatinib    mesylate, erlotinib, gefitinib, dasatinib, lapatinib, dovotinib,    axitinib, nilotinib, vandetanib, vatalinib, pazopanib, sorafenib,    sunitinib, temsirolimus, everolimus (RAD 001), vemurafenib (PLX4032    or RG7204), dabrafenib, encorafenib, selumetinib (AZD6244),    trametinib (GSK121120212), dactolisib (BEZ235), buparlisib (BKM-120;    NVP-BKM-120), BYL719, copanlisib (BAY-80-6946), ZSTK-474, CUDC-907,    apitolisib (GDC-0980; RG-7422), pictilisib (pictrelisib, GDC-0941,    RG-7321), GDC-0032, GDC-0068, GSK-2636771, idelalisib (formerly    CAL-101, GS 1101, GS-1101), MLN1117 (INK1117), MLN0128 (INK128),    IPI-145 (INK1197), LY-3023414, ipatasertib, afuresertib, MK-2206,    MK-8156, LY-3023414, LY294002, SF1126 or PI-103, sonolisib (PX-866),    or AT13148.-   (xvi) Aurora kinase inhibitors for example AT9283, barasertib    (AZD1152), TAK-901, MK0457 (VX680), cenisertib (R-763), danusertib    (PHA-739358), alisertib (MLN-8237), or MP-470;-   (xvii) CDK inhibitors for example AT7519, roscovitine, seliciclib,    alvocidib (flavopiridol), dinaciclib (SCH-727965),    7-hydroxy-staurosporine (UCN-01), JNJ-7706621, BMS-387032 (a.k.a.    SNS-032), PHA533533, ZK-304709, or AZD-5438 and including CDK4    inhibitors such as palbociclib (PD332991) and ribociclib (LEE-011);-   (xviii) PKA/B inhibitors and PKB (akt) pathway inhibitors for    example AT13148, AZ-5363, Semaphore, SF1126 and MTOR inhibitors such    as rapamycin analogues, AP23841 and AP23573, calmodulin inhibitors    (forkhead translocation inhibitors), API-2/TCN (triciribine),    RX-0201, enzastaurin HCl (LY317615), NL-71-101, SR-13668, PX-316, or    KRX-0401 (perifosine/NSC 639966);-   (xix) Hsp90 inhibitors for example onalespib (AT13387), herbimycin,    geldanamycin (GA), 17-allylamino-17-desmethoxygeldanamycin (17-AAG)    e.g. NSC-330507, Kos-953 and CNF-1010,    17-dimethylaminoethylamino-17-demethoxygeldanamycin hydrochloride    (17-DMAG) e.g. NSC-707545 and Kos-1022, NVP-AUY922 (VER-52296),    NVP-BEP800, CNF-2024 (BIIB-021 an oral purine), ganetespib    (STA-9090), SNX-5422 (SC-102112) or IPI-504;-   (xx) Monoclonal Antibodies (unconjugated or conjugated to    radioisotopes, toxins or other agents), antibody derivatives and    related agents, such as anti-CD, anti-VEGFR, anti-HER2 or anti-EGFR    antibodies, for example rituximab (CD20), ofatumumab (CD20),    ibritumomab tiuxetan (CD20), GA101 (CD20), tositumomab (CD20),    epratuzumab (CD22), lintuzumab (CD33), gemtuzumab ozogamicin (CD33),    alemtuzumab (CD52), galiximab (CD80), trastuzumab (HER2 antibody),    pertuzumab (HER2), trastuzumab-DM1 (HER2), ertumaxomab (HER2 and    CD3), cetuximab (EGFR), panitumumab (EGFR), necitumumab (EGFR),    nimotuzumab (EGFR), bevacizumab (VEGF), catumaxumab (EpCAM and CD3),    abagovomab (CA125), farletuzumab (folate receptor), elotuzumab    (CS1), denosumab (RANK ligand), figitumumab (IGF1R), CP751,871    (IGF1R), mapatumumab (TRAIL receptor), metMAB (met), mitumomab (GD3    ganglioside), naptumomab estafenatox (5T4), or siltuximab (1L6) or    immunomodulating agents such as CTLA-4 blocking antibodies and/or    antibodies against PD-1 and PD-L1 and/or PD-L2 for example    ipilimumab (CTLA4), MK-3475 (pembrolizumab, formerly lambrolizumab,    anti-PD-1), nivolumab (a anti-PD-1), BMS-936559 (anti-PD-L1),    MPDL320A, AMP-514 or MED14736 (anti-PD-L1), or tremelimumab    (formerly ticilimumab, CP-675,206, anti-CTLA-4);-   (xxi) Estrogen receptor antagonists or selective estrogen receptor    modulators (SERMs) or inhibitors of estrogen synthesis, for example    tamoxifen, fulvestrant, toremifene, droloxifene, faslodex, or    raloxifene;-   (xxii) Aromatase inhibitors and related drugs, such as exemestane,    anastrozole, letrazole, testolactone aminoglutethimide, mitotane or    vorozole;-   (xxiii) Antiandrogens (i.e. androgen receptor antagonists) and    related agents for example bicalutamide, nilutamide, flutamide,    cyproterone, or ketoconazole;-   (xxiv) Hormones and analogues thereof such as medroxyprogesterone,    diethylstilbestrol (a.k.a. diethylstilboestrol) or octreotide;-   (xxv) Steroids for example dromostanolone propionate, megestrol    acetate, nandrolone (decanoate, phenpropionate), fluoxymestrone or    gossypol,-   (xxvi) Steroidal cytochrome P450 17alpha-hydroxylase-17,20-lyase    inhibitor (CYP17), e.g. abiraterone;-   (xxvii) Gonadotropin releasing hormone agonists or antagonists    (GnRAs) for example abarelix, goserelin acetate, histrelin acetate,    leuprolide acetate, triptorelin, buserelin, or deslorelin;-   (xxviii) Glucocorticoids, for example prednisone, prednisolone,    dexamethasone;-   (xxix) Differentiating agents, such as retinoids, rexinoids, vitamin    D or retinoic acid and retinoic acid metabolism blocking agents    (RAMBA) for example accutane, alitretinoin, bexarotene, or    tretinoin;-   (xxx) Farnesyltransferase inhibitors for example tipifarnib;-   (xxxi) Chromatin targeted therapies such as histone deacetylase    (HDAC) inhibitors for example sodium butyrate, suberoylanilide    hydroxamide acid (SAHA), depsipeptide (FR 901228), dacinostat    (NVP-LAQ824), R306465/JNJ-16241199, JNJ-26481585, trichostatin A,    vorinostat, chlamydocin, A-173, JNJ-MGCD-0103, PXD-101, or apicidin;-   (xxxii) Drugs targeting the ubiquitin-proteasome pathway including    proteasome Inhibitors for example bortezomib, carfilzomib,    CEP-18770, MLN-9708, or ONX-0912; NEDD8 inhibitors; HDM2 antagonist    and deubiquitinases (DUBs);-   (xxxiii) Photodynamic drugs for example porfimer sodium or    temoporfin;-   (xxxiv) Marine organism-derived anticancer agents such as    trabectidin;-   (xxxv) Radiolabelled drugs for radioimmunotherapy for example with a    beta particle-emitting isotope (e.g., Iodine-131, Yittrium-90) or an    alpha particle-emitting isotope (e.g., Bismuth-213 or Actinium-225)    for example ibritumomab or Iodine tositumomab or alpha radium 223;-   (xxxvi) Telomerase inhibitors for example telomestatin;-   (xxxvii) Matrix metalloproteinase inhibitors for example batimastat,    marimastat, prinostat or metastat;-   (xxxviii) Recombinant interferons (such as interferon-γ and    interferon α) and interleukins (e.g. interleukin 2), for example    aldesleukin, denileukin diftitox, interferon alfa 2a, interferon    alfa 2b, or peginterferon alfa 2b;-   (xxxix) Selective immunoresponse modulators for example thalidomide,    or lenalidomide;-   (xl) Therapeutic Vaccines such as sipuleucel-T (Provenge) or    OncoVex;-   (xli) Cytokine-activating agents include Picibanil, Romurtide,    Sizofiran, Virulizin, or Thymosin;-   (xlii) Arsenic trioxide;-   (xliii) Inhibitors of G-protein coupled receptors (GPCR) for example    atrasentan;-   (xliv) Enzymes such as L-asparaginase, pegaspargase, rasburicase, or    pegademase;-   (xlv) DNA repair inhibitors such as PARP inhibitors for example,    olaparib, velaparib, iniparib, INO-1001, AG-014699, or ONO-2231;-   (xlvi) Agonists of Death receptor (e.g. TNF-related apoptosis    inducing ligand (TRAIL) receptor), such as mapatumumab (formerly    HGS-ETR1), conatumumab (formerly AMG 655), PR095780, lexatumumab,    dulanermin, CS-1008, apomab or recombinant TRAIL ligands such as    recombinant Human TRAIL/Apo2 Ligand;-   (xlvii) Immunotherapies such as immune checkpoint inhibitors; cancer    vaccines and CAR-T cell therapy;-   (xlviii) Regulators of Cell death (apoptosis) including Bcl-2    (B-cell lymphoma 2) antagonists such as venetoclax (ABT-199 or    GDC-0199), ABT-737, ABT-263, TW-37, sabutoclax, obatoclax, and MIM1    and IAP antagonists including LCL-161 (Novartis), Debio-1143    (Debiopharma/Ascenta), AZD5582, Birinapant/TL-32711 (TetraLogic),    CUDC-427/GDC-0917/RG-7459 (Genentech), JP1201 (Joyant), T-3256336    (Takeda), GDC-0152 (Genentech) or HGS-1029/AEG-40826 (HGS/Aegera);-   (xlix) Prophylactic agents (adjuncts); i.e. agents that reduce or    alleviate some of the side effects associated with chemotherapy    agents, for example    -   anti-emetic agents,    -   agents that prevent or decrease the duration of        chemotherapy-associated neutropenia and prevent complications        that arise from reduced levels of platelets, red blood cells or        white blood cells, for example interleukin-11 (e.g. oprelvekin),        erythropoietin (EPO) and analogues thereof (e.g. darbepoetin        alfa), colony-stimulating factor analogs such as granulocyte        macrophage-colony stimulating factor (GM-CSF) (e.g.        sargramostim), and granulocyte-colony stimulating factor (G-CSF)        and analogues thereof (e.g. filgrastim, pegfilgrastim),    -   agents that inhibit bone resorption such as denosumab or        bisphosphonates e.g. zoledronate, zoledronic acid, pamidronate        and ibandronate,    -   agents that suppress inflammatory responses such as        dexamethasone, prednisone, and prednisolone,    -   agents used to reduce blood levels of growth hormone and IGF-I        (and other hormones) in patients with acromegaly or other rare        hormone-producing tumours, such as synthetic forms of the        hormone somatostatin e.g. octreotide acetate,    -   antidote to drugs that decrease levels of folic acid such as        leucovorin, or folinic acid,    -   agents for pain e.g. opiates such as morphine, diamorphine and        fentanyl,    -   non-steroidal anti-inflammatory drugs (NSAID) such as COX-2        inhibitors for example celecoxib, etoricoxib and lumiracoxib,    -   agents for mucositis e.g. palifermin,    -   agents for the treatment of side-effects including anorexia,        cachexia, oedema or thromoembolic episodes, such as megestrol        acetate.

Each of the compounds present in the combinations of the invention maybe given in individually varying dose schedules and via differentroutes. As such, the posology of each of the two or more agents maydiffer: each may be administered at the same time or at different times.A person skilled in the art would know through his or her common generalknowledge the dosing regimes and combination therapies to use. Forexample, the compound of the invention may be using in combination withone or more other agents which are administered according to theirexisting combination regimen. Examples of standard combination regimensare provided below.

The taxane compound is advantageously administered in a dosage of 50 to400 mg per square meter (mg/m²) of body surface area, for example 75 to250 mg/m², particularly for paclitaxel in a dosage of about 175 to 250mg/m² and for docetaxel in about 75 to 150 mg/m² per course oftreatment.

The camptothecin compound is advantageously administered in a dosage of0.1 to 400 mg per square meter (mg/m²) of body surface area, for example1 to 300 mg/m², particularly for irinotecan in a dosage of about 100 to350 mg/m² and for topotecan in about 1 to 2 mg/m² per course oftreatment.

The anti-tumour podophyllotoxin derivative is advantageouslyadministered in a dosage of 30 to 300 mg per square meter (mg/m²) ofbody surface area, for example 50 to 250 mg/m², particularly foretoposide in a dosage of about 35 to 100 mg/m² and for teniposide inabout 50 to 250 mg/m² per course of treatment.

The anti-tumour vinca alkaloid is advantageously administered in adosage of 2 to 30 mg per square meter (mg/m²) of body surface area,particularly for vinblastine in a dosage of about 3 to 12 mg/m², forvincristine in a dosage of about 1 to 2 mg/m², and for vinorelbine indosage of about 10 to 30 mg/m² per course of treatment.

The anti-tumour nucleoside derivative is advantageously administered ina dosage of 200 to 2500 mg per square meter (mg/m²) of body surfacearea, for example 700 to 1500 mg/m², particularly for 5-FU in a dosageof 200 to 500 mg/m², for gemcitabine in a dosage of about 800 to 1200mg/m² and for capecitabine in about 1000 to 2500 mg/m² per course oftreatment.

The alkylating agents such as nitrogen mustard or nitrosourea isadvantageously administered in a dosage of 100 to 500 mg per squaremeter (mg/m²) of body surface area, for example 120 to 200 mg/m²,particularly for cyclophosphamide in a dosage of about 100 to 500 mg/m²,for chlorambucil in a dosage of about 0.1 to 0.2 mg/kg, for carmustinein a dosage of about 150 to 200 mg/m², and for lomustine in a dosage ofabout 100 to 150 mg/m² per course of treatment.

The anti-tumour anthracycline derivative is advantageously administeredin a dosage of 10 to 75 mg per square meter (mg/m²) of body surfacearea, for example 15 to 60 mg/m², particularly for doxorubicin in adosage of about 40 to 75 mg/m², for daunorubicin in a dosage of about 25to 45 mg/m², and for idarubicin in a dosage of about 10 to 15 mg/m² percourse of treatment.

The antiestrogen agent is advantageously administered in a dosage ofabout 1 to 100 mg daily depending on the particular agent and thecondition being treated. Tamoxifen is advantageously administered orallyin a dosage of 5 to 50 mg, typically 10 to 20 mg twice a day, continuingthe therapy for sufficient time to achieve and maintain a therapeuticeffect. Toremifene is advantageously administered orally in a dosage ofabout 60 mg once a day, continuing the therapy for sufficient time toachieve and maintain a therapeutic effect. Anastrozole is advantageouslyadministered orally in a dosage of about 1 mg once a day. Droloxifene isadvantageously administered orally in a dosage of about 20-100 mg once aday. Raloxifene is advantageously administered orally in a dosage ofabout 60 mg once a day. Exemestane is advantageously administered orallyin a dosage of about 25 mg once a day.

Antibodies are advantageously administered in a dosage of about 1 to 5mg per square meter (mg/m²) of body surface area, or as known in theart, if different. Trastuzumab is advantageously administered in adosage of 1 to 5 mg per square meter (mg/m²) of body surface area,particularly 2 to 4 mg/m² per course of treatment.

Where the compound of the formula (I) is administered in combinationtherapy with one, two, three, four or more other therapeutic agents(typically one or two, more typically one), the compounds can beadministered simultaneously or sequentially. In the latter case, the twoor more compounds will be administered within a period and in an amountand manner that is sufficient to ensure that an advantageous orsynergistic effect is achieved. When administered sequentially, they canbe administered at closely spaced intervals (for example over a periodof 5-10 minutes) or at longer intervals (for example 1, 2, 3, 4 or morehours apart, or even longer periods apart where required), the precisedosage regimen being commensurate with the properties of the therapeuticagent(s). These dosages may be administered for example once, twice ormore per course of treatment, which may be repeated for example every 7,14, 21 or 28 days.

It will be appreciated that the typical method and order ofadministration and the respective dosage amounts and regimes for eachcomponent of the combination will depend on the particular othermedicinal agent and compound of the present invention beingadministered, their route of administration, the particular tumour beingtreated and the particular host being treated. The optimum method andorder of administration and the dosage amounts and regime can be readilydetermined by those skilled in the art using conventional methods and inview of the information set out herein.

The weight ratio of the compound according to the present invention andthe one or more other anticancer agent(s) when given as a combinationmay be determined by the person skilled in the art. Said ratio and theexact dosage and frequency of administration depends on the particularcompound according to the invention and the other anticancer agent(s)used, the particular condition being treated, the severity of thecondition being treated, the age, weight, gender, diet, time ofadministration and general physical condition of the particular patient,the mode of administration as well as other medication the individualmay be taking, as is well known to those skilled in the art.Furthermore, it is evident that the effective daily amount may belowered or increased depending on the response of the treated subjectand/or depending on the evaluation of the physician prescribing thecompounds of the instant invention. A particular weight ratio for thepresent compound of formula (I) and another anticancer agent may rangefrom 1/10 to 10/1, more in particular from 1/5 to 5/1, even more inparticular from 1/3 to 3/1.

The compounds of the invention may also be administered in conjunctionwith non-chemotherapeutic treatments such as radiotherapy, photodynamictherapy, gene therapy; surgery and controlled diets. Radiotherapy may befor radical, palliative, adjuvant, neoadjuvant or prophylactic purposes.

The compounds of the present invention also have therapeuticapplications in sensitising tumour cells for radiotherapy andchemotherapy. Hence the compounds of the present invention can be usedas “radiosensitizer” and/or “chemosensitizer” or can be given incombination with another “radiosensitizer” and/or “chemosensitizer”. Inone embodiment the compound of the invention is for use aschemosensitiser.

The term “radiosensitizer” is defined as a molecule administered topatients in therapeutically effective amounts to increase thesensitivity of the cells to ionizing radiation and/or to promote thetreatment of diseases which are treatable with ionizing radiation.

The term “chemosensitizer” is defined as a molecule administered topatients in therapeutically effective amounts to increase thesensitivity of cells to chemotherapy and/or promote the treatment ofdiseases which are treatable with chemotherapeutics.

Many cancer treatment protocols currently employ radiosensitizers inconjunction with radiation of x-rays. Examples of x-ray activatedradiosensitizers include, but are not limited to, the following:metronidazole, misonidazole, desmethylmisonidazole, pimonidazole,etanidazole, nimorazole, mitomycin C, RSU 1069, SR 4233, EO9, RB 6145,nicotinamide, 5-bromodeoxyuridine (BUdR), 5-iododeoxyuridine (IUdR),bromodeoxycytidine, fluorodeoxyuridine (FudR), hydroxyurea, cisplatin,and therapeutically effective analogs and derivatives of the same.

Photodynamic therapy (PDT) of cancers employs visible light as theradiation activator of the sensitizing agent. Examples of photodynamicradiosensitizers include the following, but are not limited to:hematoporphyrin derivatives, Photofrin, benzoporphyrin derivatives, tinetioporphyrin, pheoborbide-a, bacteriochlorophyll-a, naphthalocyanines,phthalocyanines, zinc phthalocyanine, and therapeutically effectiveanalogs and derivatives of the same.

Radiosensitizers may be administered in conjunction with atherapeutically effective amount of one or more other compounds,including but not limited to: compounds which promote the incorporationof radiosensitizers to the target cells; compounds which control theflow of therapeutics, nutrients, and/or oxygen to the target cells;chemotherapeutic agents which act on the tumour with or withoutadditional radiation; or other therapeutically effective compounds fortreating cancer or other diseases.

Chemosensitizers may be administered in conjunction with atherapeutically effective amount of one or more other compounds,including but not limited to: compounds which promote the incorporationof chemosensitizers to the target cells; compounds which control theflow of therapeutics, nutrients, and/or oxygen to the target cells;chemotherapeutic agents which act on the tumour or other therapeuticallyeffective compounds for treating cancer or other disease. Calciumantagonists, for example verapamil, are found useful in combination withantineoplastic agents to establish chemosensitivity in tumor cellsresistant to accepted chemotherapeutic agents and to potentiate theefficacy of such compounds in drug-sensitive malignancies.

For use in combination therapy with another chemotherapeutic agent, thecompound of the formula (I) and one, two, three, four or more othertherapeutic agents can be, for example, formulated together in a dosageform containing two, three, four or more therapeutic agents i.e. in aunitary pharmaceutical composition containing all components. In analternative, the individual therapeutic agents may be formulatedseparately and presented together in the form of a kit, optionally withinstructions for their use.

In one embodiment the pharmaceutical composition comprises a compound offormula I together with a pharmaceutically acceptable carrier andoptionally one or more therapeutic agent(s)

In another embodiment the invention relates to the use of a combinationaccording to the invention in the manufacture of a pharmaceuticalcomposition for inhibiting the growth of tumour cells.

In a further embodiment the invention relates to a product containing acompound of formula I and one or more anticancer agent, as a combinedpreparation for simultaneous, separate or sequential use in thetreatment of patients suffering from cancer.

EXAMPLES

The invention will now be illustrated, but not limited, by reference tothe specific embodiments described in the following examples. Compoundsare named using an automated naming package such as AutoNom (MDL) orChemAxon Structure to Name or are as named by the chemical supplier. Inthe examples, the following abbreviations are used:

-   -   AcOH acetic acid    -   Boc tert-butyloxycarbonyl    -   Boc-Abu-OH (S)-2-(Boc-amino)butyric acid    -   BuLi butyllithium    -   CDl 1,1-carbonyldiimidazole    -   DAST Diethylaminosulfur trifluoride    -   DCM dichloromethane    -   DCMA Dicyclohexyylmethylamine    -   DIPEA N-ethyl-N-(1-methylethyl)-2-propylamine    -   DMC dimethyl carbonate    -   DMF N,N-dimethylformamide    -   DMSO dimethyl sulfoxide    -   EDC 1-ethyl-3-(3′-dimethylaminopropyl)-carbodiimide        hydrochloride    -   Et₃N triethylamine    -   EtOAc ethyl acetate    -   EtOH ethanol    -   Et₂O diethyl ether    -   HATU 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium        hexafluorophosphate)    -   HBTU        O-benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluoro-phosphate    -   HCl hydrochloric acid    -   HOAc acetic acid    -   HOAt 1-hydroxyazabenzotriazole    -   HOBt 1-hydroxybenzotriazole    -   HPLC high pressure liquid chromatography    -   IPA isopropyl alcohol    -   KHMDS potassium hexamethyldisilazide    -   LiHMDS lithium bis(trimethylsilyl)amide    -   MeCN acetonitrile    -   MeOH methanol    -   mins. minutes    -   MS mass spectrometry    -   MW microwave    -   NaBH(OAc)₃ sodium triacetoxyborohydride    -   NaOtBu potassium tert-butoxide    -   NMP N-methyl-2-pyrrolidinone    -   NMR nuclear magnetic resonance spectroscopy    -   Pd₂(dba)₃ tris(dibenzylideneacetone)dipalladium (o)    -   Pd(OAc)₂ palladium (2) acetate    -   Pd(PPh₃)₄ tetrakis(triphenylphosphine)palladium (0)    -   petrol petroleum ether fraction with boiling point range 40-60°        C.    -   PyBrop bromo-tris-pyrrolidino-phosphonium hexafluorophosphate    -   RT room temperature    -   SiO₂ silica    -   TBTU N,N,N′,N′-tetramethyl-O-(benzotriazol-1-yl)uronium        tetrafluoroborate    -   TEA triethylamine    -   TFA trifluoroacetic acid    -   THF tetrahydrofuran    -   UV Ultraviolet

Column Chromatography

Purification using column chromatography can be achieved, for exampleusing a Biotage automated flash purification system with UV monitoringat 298 nm and collection at 254 nm. Biotage automated chromatographypre-packed silica cartridges were used in most cases. Where stated, thepurification of some compounds was performed using Biotage C18 reversedphase silica columns, which have octadecyl (end-capped) functionalisedsilica or Biotage KP-NH cartridges were used for the separation ofhighly polar compounds, which uses primary amine bonded silica.

Where necessary, semi-preparative HPLC can be carried out, for exampleusing one of the following machines: (i) Varian Prostar Modular HPLCsystem with a binary pumping system, UV detector and fraction collectorand controlled by Varian Star software. (ii) Agilent 1200 HPLC systemwith a binary pump, autosampler, fraction collector and diode arraydetector and controlled by Agilent ChemStation software.

Analytical LC-MS System Description

In the following examples, many of the compounds prepared werecharacterised by mass spectroscopy using the systems and suitableoperating conditions set out below. Where atoms with different isotopesare present and a single mass quoted, the mass quoted for the compoundis the monoisotopic mass (i.e. ³⁵Cl; ⁷⁹Br etc.). Several systems can beused, as described below, and these can be equipped with, and can be setup to run under, closely similar operating conditions. Possibleoperating conditions are also described below.

Agilent 1200SL-6140 LC-MS System—RAPID:

HPLC System: Agilent 1200 series SL

Mass Spec Detector: Agilent 6140 single quadrupole

Second Detector: Agilent 1200 MWD SL

Agilent MS Running Conditions:

Capillary voltage: 3000V on ES pos (2700V on ES Neg)

Fragmentor/Gain: 190 on ES pos (160 on ES neg)

Gain: 1

Drying gas flow: 12.0 L/min

Gas Temperature: 345° C.

Nebuliser Pressure: 60 psig

Scan Range: 125-800 amu

Ionisation Mode: ElectroSpray Positive-Negative switching

Shimadzu Nexera LC-MS System

HPLC System: Shimadzu SIL-30AC autosampler/2× Shimadzu LC-30AD pumps

Mass Spec Detector: Shimadzu LCMS-2020 single quadrupole MS

Second Detector: Shimadzu SPD-M20A diode array detector

Shimadzu MS Running Conditions:

Qarray DC voltage: 20V on ES Pos (−20V on ES Neg)

Drying gas flow: 20.0 L/min

DL Temperature: 300° C.

Heat Block Temperature: 350° C.

Nebulising Gas Flow: 1.5 L/min

Scan Range: 100-750 amu

Ionisation Mode: ElectroSpray Positive-Negative switching

Mass Directed Purification LC-MS System

Preparative LC-MS is a standard and effective method used for thepurification of small organic molecules such as the compounds describedherein. The methods for the liquid chromatography (LC) and massspectrometry (MS) can be varied to provide better separation of thecrude materials and improved detection of the samples by MS.Optimisation of the preparative gradient LC method will involve varyingcolumns, volatile eluents and modifiers, and gradients. Methods are wellknown in the art for optimising preparative LC-MS methods and then usingthem to purify compounds. Such methods are described in Rosentreter U,Huber U.; Optimal fraction collecting in preparative LC/MS; J CombChem.; 2004; 6(2), 159-64 and Leister W, Strauss K, Wisnoski D, Zhao Z,Lindsley C., Development of a custom high-throughput preparative liquidchromatography/mass spectrometer platform for the preparativepurification and analytical analysis of compound libraries; J CombChem.; 2003; 5(3); 322-9.

Several systems for purifying compounds via preparative LC-MS aredescribed below although a person skilled in the art will appreciatethat alternative systems and methods to those described could be used.In particular, normal phase preparative LC based methods might be usedin place of the reverse phase methods described here. Most preparativeLC-MS systems utilise reverse phase LC and volatile acidic modifiers,since the approach is very effective for the purification of smallmolecules and because the eluents are compatible with positive ionelectrospray mass spectrometry. Employing other chromatographicsolutions e.g. normal phase LC, alternatively buffered mobile phase,basic modifiers etc as outlined in the analytical methods describedabove could alternatively be used to purify the compounds.

Preparative LC-MS System Description:

Waters Fractionlynx System:

Hardware:

2767 Dual Loop Autosampler/Fraction Collector

2525 preparative pump

CFO (column fluidic organiser) for column selection

RMA (Waters reagent manager) as make up pump

Waters ZQ Mass Spectrometer

Waters 2996 Photo Diode Array detector

Waters ZQ Mass Spectrometer

Software:

Masslynx 4.1

Waters MS Running Conditions:

Capillary voltage: 3.5 kV (3.2 kV on ES Negative)

Cone voltage: 25 V

Source Temperature: 120° C.

Multiplier: 500 V

Scan Range: 125-800 amu

Ionisation Mode: ElectroSpray Positive or

ElectroSpray Negative

Agilent 1100 LC-MS Preparative System:

Hardware:

Autosampler: 1100 series “prepALS”

Pump: 1100 series “PrepPump” for preparative flow gradient and 1100series “QuatPump” for pumping modifier in prep flow

UV detector: 1100 series “MWD” Multi Wavelength Detector

MS detector: 1100 series “LC-MSD VL”

Fraction Collector: 2×“Prep-FC”

Make Up pump: “Waters RMA”

Agilent Active Splitter

Software:

Chemstation: Chem32

Agilent MS Running Conditions:

Capillary voltage: 4000 V (3500 V on ES Negative)

Fragmentor/Gain: 150/1

Drying gas flow: 13.0 L/min

Gas Temperature: 350° C.

Nebuliser Pressure: 50 psig

Scan Range: 125-800 amu

Ionisation Mode: ElectroSpray Positive or

-   -   ElectroSpray Negative

Columns:

A range of commercially available columns—both achiral and chiral—may beused such that, in conjunction with the changes in mobile phase, organicmodifier and pH, they enabled the greatest cover in terms of a broadrange of selectivity. All columns were used in accordance with themanufacturers recommended operating conditions. Typically 5 micronparticle sized columns were used where available. For example, columnsfrom Waters (including but not limited to XBridge Prep Phenyl 5μ OBD100×19 mm, XBridge Prep C18 5μ OBD 100×19 mm, Waters Atlantis Prep T3OBD 5μ 100×19 mm and SunFire Prep C18 OBD 5μ 100×19 mm), Phenomenex(including but not limited to Synergy MAX-RP and LUX™ Cellulose-2),Astec (Chirobiotic™ columns including but not limited to V, V2 and T2)and Diacel® (including but not limited to Chiralpak® AD-H) wereavailable for screening.

Eluents:

Mobile phase eluent was chosen in conjunction with column manufacturersrecommended stationary phase limitations in order to optimise a columnsseparation performance.

Methods:

According to the analytical trace the most appropriate preparativechromatography type was chosen. A typical routine was to run ananalytical LC-MS using the type of chromatography (low or high pH) mostsuited for compound structure. Once the analytical trace showed goodchromatography a suitable preparative method of the same type waschosen.

Solvent:

All compounds were usually dissolved in 100% MeOH or 100% DMSO or 90:10Methanol:Water+0.2% Formic Acid.

Supercritical Fluid Chromatography (SFC)

In some cases, final compounds were purified by Supercritcal FluidChromatography (SFC) using a Waters Thar Prep100 preparative SFC system(P200 CO2 pump, 2545 modifier pump, 2998 UV/VIS detector, 2767 liquidhandler with Stacked Injection Module). The Waters 2767 liquid handleracted as both auto-sampler and fraction collector.

The column used for the preparative purification of the compounds was aDiacel Chiralpak IA/IB/IC, YMC Amylose/Cellulose C or Phenomenex LuxCellulose-4 at 5 um 20-21.2×250 mm unless otherwise stated.

Appropriate isocratic methods were selected based on methanol, ethanolor isopropanol solvent systems under un-modified or basic conditions.The standard method used was typically 5-55% modifier/CO2, 100 ml/min,120 Bar backpressure, 40° C. column temperature.

All compounds were screened analytically prior to the purification step.Each sample was run under both un-modified and basic conditions (5.0 ulinjection, 5/95 gradient for 5 minutes) across ethanol, methanol andisopropanol. If necessary, secondary screen across extended solventssuch as acetonitrile, ethyl acetate and THF may also be considered. Adecision was then made by the analyst as to what pH and which isocraticcondition to use depending on where the desired product elutes and theseparation achieved.

The modifier used under basic conditions was diethyl amine (0.1% V/V).Occasionally formic acid (0.1% V/V) may be used as an acidic modifier.

The purification was controlled by Waters Fractionlynx software throughmonitoring at 210-400 nm and triggered a threshold collection value at260 nm unless otherwise started. Collected fractions were analysed bySFC (Waters/Thar SFC systems with Waters SQD). The fractions thatcontained the desired product were concentrated by vacuumcentrifugation.

From the information provided someone skilled in the art could purifythe compounds described herein by preparative LC-MS.

Synthetic Methods

By following methods similar and/or analogous to general proceduresbelow, the compounds set out below were prepared.

The following synthetic procedures are provided for illustration of themethods used; for a given preparation or step the precursor used may notnecessarily derive from the individual batch synthesised according tothe step in the description given.

Where a compound is described as a mixture of twodiastereoisomers/epimers, the configuration of the stereocentre is notspecified and is represented by straight lines.

As understood by a person skilled in the art, compounds synthesisedusing the protocols as indicated may exist as a solvate e.g. hydrate,and/or contain residual solvent or minor impurities. Compounds isolatedas a salt form, may be integer stoichiometric i.e. mono- or di-salts, orof intermediate stoichiometry.

Some of the compounds below are isolated as the salt, for exampledepending on the acid used in the purification method. Some compoundsare isolated as the free base.

Compounds containing a single stereocentre (R-configuration) at the3-position are typically isolated as a single isomer using preparativechiral HPLC (as described in general methods); at (or towards) the finalstage of the synthetic sequence. In these cases the stereochemistry atthe 3-position is designated in accordance with IUPAC, using ‘hashed’ or‘solid’ wedged lines. Unless stated otherwise, a straight line at astereocentre indicates the compound exists as a mixture of both isomers.

An example(3R)-3-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-3-{[1-(hydroxymethyl)cyclopropyl]methoxy}-6-(2-hydroxypropan-2-yl)-2,3-dihydro-1H-isoindol-1-oneis shown in Figure A.

Figure A: Example showing purification of 3R-isomer by chiral HPLC

Compounds containing a second stereocentre (e.g. adjacent to the6-position) are typically isolated as a single isomer by preparativeachiral and/or chiral HPLC. In these cases, the stereochemistry at the 3position is designated in the usual fashion, using ‘hashed’ or ‘solid’wedged lines. An asterisk (*) at the second stereocentre indicates one(or both) of the diastereoisomers associated with this position was/wereisolated separately. For example, the 2 isomers of(3R)-2-[(4-chloro-2-methanesulfonylphenyl)methyl]-3-(4-chlorophenyl)-4-fluoro-6-[1-hydroxy-1-(1-methyl-1H-pyrazol-4-yl)ethyl]-3-[(1-hydroxycyclopropyl)methoxy]-2,3-dihydro-1H-isoindol-1-onewere separated by preparative achiral and/or chiral HPLC to give twoseparate Examples (Figure B).

Note: Depending on the specific substitution pattern, the numberingsystem in some analogues may differ, according to the formal conventionof nomenclature.

Figure B: Asterisk (*) means the two isomers were separated and isolatedto give the two diastereoisomeric examples (Example 75 and 76)

In other cases, isomers were separated at an intermediate stage in thesynthesis and only one isomer progressed to the final Example. Therelevant isomers can be characterised by either optical rotation oflinearly polarized light and/or or relative retention time on a chiralHPLC column. In these cases, an asterisk (*) indicates that the compoundwas isolated as a single isomer. This is illustrated by Example 80(Figure C)

Figure C: Synthesis of Example 80,(3R)-2-[(4-chloro-2-methanesulfonylphenyl)methyl]-3-(4-chlorophenyl)-4-fluoro-6-[1-hydroxy-1-(1-methylpiperidin-4-yl)ethyl]-3-{[1-(hydroxymethyl)cyclopropyl]methoxy}-2,3-dihydro-1H-isoindol-1-one.Example is derived from the levorotary enantiomer of compound (3),followed by a preparative chiral HPLC at the final stage.

The optical isomers may be characterised by their optical activity (i.e.as + and − isomers, or d and l isomers). The stereocentre can alsoassigned as “R or S” according to the nomenclature developed by Cahn,Ingold and Prelog, see Advanced Organic Chemistry by Jerry March, 4^(th)Edition, John Wiley & Sons, New York, 1992, pages 109-114, and see alsoCahn, Ingold & Prelog, Angew. Chem. Int. Ed. Engl., 1966, 5, 385-415.

Optical isomers can be separated by a number of techniques includingchiral chromatography (chromatography on a chiral support) and suchtechniques are well known to the person skilled in the art.

As an alternative to chiral chromatography, optical isomers of basiccompounds can be separated by forming diastereoisomeric salts withchiral acids such as (+)-tartaric acid, (−)-pyroglutamic acid,(−)-di-toluoyl-L-tartaric acid, (+)-mandelic acid, (−)-malic acid, and(−)-camphorsulfonic acid, separating the diastereoisomeric salts bypreferential crystallisation, and then dissociating the salts to givethe individual enantiomer of the free base. Likewise, optical isomers ofacidic compounds can be separated by forming diastereoisomeric saltswith chiral amines such as Brucine, Cinchonidine, quinine etc.

Additionally enantiomeric separation can be achieved by covalentlylinking a enantiomerically pure chiral auxiliary onto the compound andthen performing diastereoisomer separation using conventional methodssuch as chromatography. This is then followed by cleavage of theaforementioned covalent linkage to generate the appropriateenantiomerically pure product. Examples could include making mentholesters of an acidic compound.

Where compounds of the formula (I) exist as two or more optical isomericforms, one enantiomer in a pair of enantiomers may exhibit advantagesover the other enantiomer, for example, in terms of biological activity.Thus, in certain circumstances, it may be desirable to use as atherapeutic agent only one of a pair of enantiomers, or only one of aplurality of diastereoisomers.

Accordingly, the invention provides compositions containing a compoundof the formula (I) having one or more chiral centres, wherein at least55% (e.g. at least 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95%) of thecompound of the formula (I) is present as a single optical isomer (e.g.enantiomer or diastereoisomer). In one general embodiment, 99% or more(e.g. substantially all) of the total amount of the compound of theformula (I) may be present as a single optical isomer (e.g. enantiomeror diastereoisomer).

Compounds encompassing double bonds can have an E (entgegen) or Z(zusammen) stereochemistry at said double bond. Substituents on bivalentcyclic or (partially) saturated radicals may have either the cis- ortrans-configuration. The terms cis and trans when used herein are inaccordance with Chemical Abstracts nomenclature (J. Org. Chem. 1970, 35(9), 2849-2867), and refer to the position of the substituents on a ringmoiety.

Of special interest are those compounds of formula (I) which arestereochemically pure. When a compound of formula (I) is for instancespecified as R, this means that the compound is substantially free ofthe S isomer. If a compound of formula (I) is for instance specified asE, this means that the compound is substantially free of the Z isomer.The terms cis, trans, R, S, E and Z are well known to a person skilledin the art.

Examples 1-137 Preparation 1. 4-Fluoro-2-hydroxybenzaldehyde

To a mixture of 3-fluorophenol (415 mg, 3.70 mmol) and anhydrous MgCl₂powder (1.06 g, 11.1 mmol) in anhydrous acetonitrile (20 mL) was addedanhydrous triethylamine (1.94 mL) and paraformaldehyde (811 mg, 27.0mmol). The mixture was heated to reflux for 4.25 h, during which timethere was a colour change from white to pink to yellow. The reactionmixture was cooled to room temperature and 5% aqueous HCl was added (20mL). The product was extracted with EtOAc (2×50 mL) and the combinedorganic extracts washed with H₂O (3×50 mL), brine (50 mL), dried overanhydrous MgSO₄ and the solvent removed in vacuo. FCC[dichloromethane-methanol (100:0)→(97:3)] of the crude residue affordedthe title Preparation 1 (367 mg, 71%) as a white solid; R_(f) 0.83 (10%MeOH:CH₂Cl₂); ¹H NMR (500 MHz, CDCl₃) δ 11.35 (1H, d, J=1.6 Hz, CHO),9.82 (1H, s), 7.55 (1H, dd, J=6.3 and 8.6 Hz), 6.71 (1H, dt, J=2.4 and8.3 Hz) and 6.66 (1H, dd, J=2.4 and 10.4 Hz), ¹⁹F NMR (470.7 MHz, CDCl₃)δ −97.53 (m).

Preparation 2:N′-(5′-Bromo-2′-hydroxybenzylidene)-4-chlorobenzohydrazide

By following a similar procedure to Preparation3,5-bromo-2-hydroxybenzaldehyde (10 g, 49.7 mmol) and4-chlorobenzhydrazide (8.5 g, 49.7 mmol) gave Preparation 2 as an offwhite solid which was used in the next step without further purification(16.5 g, 94%), δ_(max)/cm⁻¹ 1014, 1266, 1354, 1476, 1642, 3069, 3218;δ_(H)(500 MHz; DMSO) 6.91 (1H, d, J=8.6, 3′-H), 7.44 (1H, dd, J=2.3,8.7, 4′-H), 7.61-7.67 (2H, m, Ar—H), 7.81 (1H, d, J=2.3, 6′-H),7.94-8.01 (2H, m, Ar—H), 8.62 (1H, s, 1′-CH), 11.2 (1H, br. s, NH),12.24 (1H, br. s, OH).

Preparation 3:(E)-N′-(5-Bromo-3-fluoro-2-hydroxybenzylidene)-4-chlorobenzohydrazide

To a solution of 5-bromo-3-fluoro-2-hydroxybenzaldehyde (1.06 g, 4.83mmol) in acetic acid (23 mL) was added 4-chlorobenzhydrazide (824 mg,4.83 mmol) at room temperature and the resulting mixture stirred for 15min. The suspension was poured onto water (20 mL) at 0° C. and theresulting precipitate collected by filtration. The solid was washed withwater (3×20 mL), then petrol (3×20 mL) and the product dried overnightin the vacuum oven to afford(E)-N′-(5-bromo-3-fluoro-2-hydroxybenzylidene)-4-chlorobenzohydrazidePreparation 3 (1.69 g, 94%) as a pale yellow solid, which was usedwithout further purification; R_(f) 0.84 (10% MeOH:CH₂Cl₂);λ_(max)(EtOH)/nm 237.8, 292.6, 303.6 and 333.0; IR (cm⁻¹) 1098, 1158,1242, 1463, 1521, 1591, 1660, 2360 and 3261; mp 245° C. (decomp.); 1HNMR (500 MHz, DMSO) δ 12.39 (1H, br.s), 11.64 (1H, br.s), 8.63 (1H, s,HC═N), 7.98 (1H, d, J=8.5 Hz, 2×ArH), 7.69 (1H, s, ArH), 7.65 (2H, d,J=8.5 Hz, 2×ArH) and 7.60 (1H, dd, J=2.2 and 10.4 Hz, ArH). LRMS (ESI+)m/z 371.2 [M]⁺.

Preparation 4: 5-Bromo-2-(4-chlorobenzoyl)benzaldehyde

By following a similar procedure to preparation 5,N′-(5′-bromo-2′-hydroxybenzylidene)-4-chlorobenzohydrazide (Preparation2) (16.53 g, 46.7 mmol), Pb(OAc)₄ (20.7 g, 46.7 mmol) and THF (492 mL).Purified on silica gel eluting with 20→85% EtOAc/Hexane to give thePreparation 4 as an orange solid (13.41, 88%). δ_(max)/cm⁻¹ 764, 927,1189, 1277, 1585, 1663, 1698, 2354, 2840, 3086; δ_(H)(500 MHz; CDCl₃)7.37 (1H, d, J=8.2, 3-H), 7.43-7.46 (1H, m, Ar—H), 7.70-7.73 (2H, m,Ar—H), 7.82 (1H, dd, J=2.0, 7.9, 4-H), 8.14 (1H, d, J=2.0, 6-H). m/z(ESI+) 323 (M+80%) 325 (100%).

Preparation 5: 5-Bromo-2-(4-chlorobenzoyl)-3-fluorobenzaldehyde

To a suspension of(E)-N′-(5-bromo-4-fluoro-2-hydroxybenzylidene)-4-chlorobenzohydrazide(Preparation 3) (1.67 g, 4.49 mmol) in THF (45 mL) was added Pb(OAc)₄(1.99 g, 4.49 mmol) portionwise. The resulting orange solution wasstirred at room temperature for 2 h and then filtered through Celite®,eluting with EtOAc (30 mL). The organics were washed with saturatedaqueous NaHCO₃ (50 mL), brine (50 mL) dried over anhydrous Na₂SO₄, andthe solvent removed in vacuo. FCC [petrol-ethyl acetate (100:0)→(95:5)]of the crude residue afforded5-Bromo-2-(4-chlorobenzoyl)-3-fluorobenzaldehyde Preparation 5 (1.29 g,84%) as a yellow solid; R_(f) 0.87 (40% EtOAc:Petrol); λ_(max) (EtOH)/nm201.8 and 258.4; IR (cm⁻¹) 1095, 1249, 1271, 1586, 1649, 1710, 2920 and3072; mp 120.6-122.0° C.; 1H NMR (500 MHz, DMSO) δ 9.87 (1H, s, CHO),8.27 (1H, d, J=1.6 Hz, HCCBr), 8.15 (1H, dd, J=1.6 and 8.8 Hz, HCCF)7.75 (2H, d, J=8.5 Hz, 2×Ar) and 7.59 (2H, d, J=8.5 Hz, 2×ArH). LRMS(ESI+) m/z 341.2 [M]⁺.

Preparation 6: 5-Bromo-2-(4-chlorobenzoyl)benzoic acid

Following procedures similar to these described in Preparation 7;5-bromo-2-(4-chlorobenzoyl)benzaldehyde (Preparation 4) (7.4 g, 22.9mmol), sodium chlorite (2.9 g, 29.7 mmol), sulfamic acid (2.77 g, 30.6mmol), acetonitrile (213 mL) and water (72 mL) gave Preparation 6 as abeige solid and was used in the next step without further purification(7.4 g, 95%). δ_(max)/cm⁻¹ 1014, 1090, 1252, 1270, 1288, 1305, 1423,1481, 1582, 1671, 2551, 2658, 2800; δ_(H)(500 MHz; DMSO) 7.44 (1H, d,J=8.0, 4-H), 7.56-7.60 (2H, m, Ar—H), 7.63-7.67 (2H, m, Ar—H), 7.96 (1H,dd, J=2.0, 8.0, 4-H), 8.11 (1H, d, J=2.0, 6-H), 13.64 (1H, br s, COOH).m/z (ESI−) 337 (75%) 339 (M+100%) 341 (25%).

Preparation 7: 5-Bromo-2-(4-chlorobenzoyl)-3-fluorobenzoic acid

To a solution of 5-Bromo-2-(4-chlorobenzoyl)-3-fluorobenzaldehyde(Preparation 5) (1.27 g, 3.71 mmol) in acetonitrile (48 mL) was added asolution of sodium chlorite (436 mg, 4.82 mmol) in water (5.4 mL),followed by a solution of sulfamic acid (468 mg, 4.82 mmol) in water(5.4 mL). The resulting yellow solution was stirred at room temperaturefor 3 h and then the solvent removed in vacuo. The resulting yellowsolid was dissolved in ethyl acetate (30 mL) and washed with water (30mL), brine (30 mL), dried over anhydrous Na₂SO₄ and the solvent removedto give 5-bromo-2-(4-chlorobenzoyl)-3-fluorobenzoic acid Preparation 7(1.33 g, 100%) as a pale yellow solid, which was used without anyfurther purification; R_(f) 0.23 (10% MeOH:CH₂Cl₂); λ_(max) (EtOH)/nm207.0 and 258.0; IR (cm⁻¹) 1087, 1269, 1397, 1590, 1678, 1711 and 3072;mp 155° C. (decomp.); ¹H NMR (500 MHz, DMSO) δ 13.93 (1H, br. s, COOH),8.07 (1H, dd, J=1.5 and 9.0 Hz, HCCF), 8.00 (1H, d, J=1.5 Hz, HCCBr),7.74 (2H, d, J=8.5 Hz, 2×Ar) and 7.59 (2H, d, J=8.5 Hz, 2×ArH). LRMS(ESI−) m/z 357.0 [M]⁻.

Preparation 8:6-Bromo-2-(4-chlorobenzyl)-3-(4-chlorophenyl)-3-hydroxyisoindolin-1-one

The title compound was prepared from 5-bromo-2-(4-chlorobenzoyl)benzoicacid (7.4 g, 21.8 mmol) using a procedure similar to that described forPreparation 9. The product was obtained as a yellow solid (6.78 g, 66%)m/z (ESI−) 462 (100%) (M+H⁺)⁺

Preparation 9:6-Bromo-2-(4-chlorobenzyl)-3-(4-chlorophenyl)-4-fluoro-3-hydroxyisoindolin-1-one

To a solution of 5-bromo-2-(4-chlorobenzoyl)-3-fluorobenzoic acid(Preparation 7) (509 mg, 1.42 mmol) in anhydrous THF (7.1 mL) was addedthionyl chloride (0.21 mL, 2.85 mmol) and a catalytic quantity of DMF (1drop) and the yellow mixture stirred at room temperature for 4 h, thenconcentrated under reduced pressure. The residue was dissolve inanhydrous THF (7.1 mL) and 4-chlorobenzylamine (0.19 mL, 1.56 mmol) andHunigs base (0.27 mL, 1.56 mmol) were added and the mixture stirred atroom temperature for 16 h. The reaction was diluted with EtOAc (20 mL)and the solution washed with water (3×20 mL) and brine (20 mL), driedover anhydrous MgSO₄ and concentrated in vacuo to give a dark orangeoil. FCC [petrol-ethyl acetate (100:0)→(95:5)→(80:20)] of the cruderesidue afforded6-bromo-2-(4-chlorobenzyl)-3-(4-chlorophenyl)-4-fluoro-3-hydroxyisoindolin-1-onePreparation 9 (624 mg, 91%) as a pale yellow solid; LRMS (ESI−) m/z480.1 [M−H]⁻.

Preparation 10:6-Bromo-2-(4-chlorobenzyl)-3-(4-chlorophenyl)-3-((1-(hydroxymethyl)cyclopropyl)methoxy)isoindolin-1-one

To a solution of6-bromo-2-(4-chlorobenzyl)-3-(4-chlorophenyl)-3-hydroxyisoindolin-1-one(Preparation 8) (1 g, 2.1 mmol) and 1,1-Bis(hydroxymethyl)cyclopropane(0.604 mL, 6.3 mmol) in DCE (21 mL) was added InBr₃ (76 mgs, 0.21 mmol)and the resulting mixture was heated to 95° C. for 3 hours. The reactionwas cooled to room temperature before being washed with water, brine,and the organic phase dried (MgSO₄), filtered and conc. in vacuo.Purification on silica gel (Biotage SP4) eluting with 20%→95% EtOAc/petgave Preparation 10 as a brown gum (921 mgs; 80%). (500 MHz, CDCl₃)0.10-0.19 (2H, m), 0.37-0.46 (2H, m), 1.53 (1H, t), 2.65 (1H, d), 2.81(1H, d), 3.36 (1H, dd), 3.50 (1H, dd), 4.17 (1H, d), 4.50 (1H, d), 7.01(1H, d), 7.08-7.22 (8H, m), 7.63 (1H, dd), 8.02 (1H, d).

Preparation 11:6-Bromo-3-((1-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)methoxy)-2-(4-chlorobenzyl)-3-(4-chlorophenyl)isoindolin-1-one

Preparation 10 (0.8 g, 1.46 mmol), imidazole (0.370 g, 5.44 mmol),TBDMSCl (0.496 g, 3.29 mmol) in THF (10 mL/0.7 mmol) was heated at 85°C. for 7 hours. After work-up, the crude material was purified usingchromatography on silica (Pet:EtOAc 1:0 to 4:1) to give the desiredproduct Preparation 11 as a colorless oil (0.928 g, 1.403 mol) in 96 ¹HNMR (500 MHz, CDCl₃) δ (ppm) −0.02 (s, 3H), 0.00 (s, 3H), 0.06-0.15 (m,2H), 0.30-0.43 (m, 2H), 0.83 (s, 9H), 2.61 (d, 1H), 2.87 (d, 1H), 3.35(d, 1H), 3.65 (d, 1H), 4.30 (d, 1H), 4.37 (d, 1H), 6.97 (d, 1H), 7.04(d, 2H), 7.10 (d, 2H, J=8.5 Hz, Ar—H), 7.12-7.20 (m, 4H, Ar—H), 7.60(dd, 1H), 8.02 (d, 1H); MS(ES+) m/z 456.4 [M+H]⁺.

Preparation 12:6-Bromo-2-(4-chlorobenzyl)-3-(4-chlorophenyl)-4-fluoro-3-((1-(hydroxymethyl)cyclopropyl)methoxy)isoindolin-1-one

To a solution of6-bromo-2-(4-chlorobenzyl)-3-(4-chlorophenyl)-4-fluoro-3-hydroxyisoindolin-1-one(Preparation 9) (603 mg, 1.25 mmol) in anhydrous THF (7 mL) was addedthionyl chloride (0.18 mL, 2.50 mmol) and a catalytic quantity of DMF (2drops) and the orange mixture stirred at room temperature for 4 h, thenconcentrated under reduced pressure. The residue was dissolved inanhydrous THF and then a solution of 1,1-bis(hydroxymethyl)cyclopropane(0.24 mL, 2.50 mmol) and K₂CO₃ (345 mg, 2.50 mmol) were added and thereaction mixture stirred at room temperature for 18 h. The reactionmixture was diluted with EtOAc (10 mL) and washed with water (3×20 mL),brine (20 mL), dried over Na₂SO₄, filtered and the solvent removed invacuo. FCC [petrol-ethyl acetate (100:0)→(80:20)] of the crude residueafforded6-bromo-2-(4-chlorobenzyl)-3-(4-chlorophenyl)-4-fluoro-3-((1-(hydroxymethyl)cyclopropyl)methoxy)isoindolin-1-onePreparation 12 (389 mg, 55%) as a yellow gum; ¹H NMR (500 MHz, DMSO) δ0.13 (2H, m), 0.34 (2H, m), 2.81 (1H, d), 2.86 (1H, d), 3.28 (1H, dd),3.35 (1H, dd), 4.28 (1H, d), 4.34 (1H, d), 7.05 (2H, d), 7.19 (2H, d,J=8.5 Hz, 2×ArH), 7.25 (2H, d, J=8.4 Hz, 2×ArH), 7.30 (2H, d), 7.82 (1H,dd) and 7.89 (1H, dLRMS (ESI+) m/z 464.2 [M-C₅H₉O₂]⁺

Preparation 13:2-(4-Chlorobenzyl)-3-(4-chlorophenyl)-3-((1-(hydroxymethyl) cyclopropyl)methoxy)-6-(prop-1-en-2-yl)isoindolin-1-one

A suspension of isopropenylboronic acid ester (239 μL, 1.27 mmol),6-bromo-2-(4-chlorobenzyl)-3-(4-chlorophenyl)-3-((1-(hydroxymethyl)cyclopropyl)methoxy)isoindolin-1-one (Preparation 10) (465 g, 0.85mmol), NaOH (35.7 mgs, 0.89 mmol), and N,N-dicyclohexylmethyl amine(0.191 mL, 0.894 mmol) in THF (4.63 mL) was degassed for 10 minutesbefore the addition of Pd(dppf)Cl₂ (62 mgs, 0.09 mmol). The resultingmixture was heated to a rapid reflux for 3 hours. The reaction wascooled to room temperature, diluted with DCM and washed with HCl (1M),water, brine, dried (MgSO₄), filtered and conc. in vacuo. Purificationon silica gel eluting with 30% EtOAc/Hexanes gave Preparation 13 as awhite foam (316 mgs; 73%); m/z (ESI+) 508.4 (10%), 406.3, 408.3 (70%).

Preparation 14:2-(4-Chlorobenzyl)-3-(4-chlorophenyl)-4-fluoro-3-((1-(hydroxymethyl)cyclopropyl)methoxy)-6-(prop-1-en-2-yl)isoindolin-1-one

6-bromo-2-(4-chlorobenzyl)-3-(4-chlorophenyl)-4-fluoro-3-((1-(hydroxymethyl)cyclopropyl)methoxy)isoindolin-1-one(Preparation 12) (194 mg, 0.343 mmol) was dissolved in anhydrous THF(4.6 mL) and powdered NaOH (14 mg, 0.343 mmol), DCMA (0.07 mL, 0.343mmol) and iso-propenylboronic acid pinacol ester (0.1 mL, 0.514 mmol)were added sequentially at room temperature under a N₂ atmosphere. Thesolution was degassed with N₂ for 20 min, then Pd(dppf)Cl₂.CH₂Cl₂ (28mg, 0.100 mmol) was added and the solution heated at reflux for 3.5 h.After cooling to room temperature, the reaction mixture was filteredthrough Celite®, rinsed with EtOAc, then transferred to a separatingfunnel and washed with 1M aq. HCl (20 mL), brine (20 mL), dried overNa₂SO₄, filtered and the solvent removed in vacuo. FCC [petrol-ethylacetate (100:0)→(85:15))→(70:30)] of the crude residue, followed bypreparative HPLC, afforded2-(4-chlorobenzyl)-3-(4-chlorophenyl)-4-fluoro-3-((1-(hydroxymethyl)cyclopropyl)methoxy)-6-(prop-1-en-2-yl)isoindolin-1-onePreparation 14 (150 mg, 83%) as a pale yellow gum; LRMS (ESI+) m/z 426.3[M-C₅H₉O₂]⁺.

Preparation 15:6-Acetyl-2-(4-chlorobenzyl)-3-(4-chlorophenyl)-3-((3′-(hydroxymethyl)cyclopropyl) methoxy)isoindolin-1-one

To a solution of2-(4-chlorobenzyl)-3-(4-chlorophenyl)-3-((1-(hydroxymethyl) cyclopropyl)methoxy)-6-(prop-1-en-2-yl)isoindolin-1-one (preparation 13) (64 mgs,0.125 mmol) in dioxane/H₂O (3:1, 1.23 mL) at room temperature was added2,6-Lutidine (30 μL, 0.251 mmol), OsO₄ (˜1 mg, 0.0025 mmol) and NaIO₄(106 mg, 0.5 mmol) and the resulting mixture stirred until TLC indictedthe complete consumption of the starting material. The reaction wasdiluted with water and DCM and the organic phase separated. The aqueouslayer was extracted DCM (×3) and the combined organic phases washed withbrine, dried (MgSO₄) and conc. in vacu. Purification on silica gel(Biotage SP4) eluting with 20%→85% EtOAc/Pet gave Preparation 15 aswhite foam (37 mgs; 60%). HRMS (ESI+) 510.121 (MH⁺).

Preparation 16:3-(4-chlorophenyl)-2-((S)-1-(4-chlorophenyl)ethyl)-3-hydroxy-6-(prop-1-en-2-yl)isoindolin-1-one

The title compound was prepared using a mixture of Preparations 25a and25b, by following a procedure similar to that described for Preparation13. The crude material was purified using chromatography on silica(Pet:EtOAc 1:0 to 2:1) to give the desired diastereoisomers as a beigesolid (2.255 g, 5.14 mmol).

Preparation 16a R_(f)=0.30 (Pet:EtOAc/9:1); MS(ES+) m/z 484.3 [M+H

Preparation 16b: R_(f)=0.15 (Pet:EtOAc/9:1);

Preparation 17:(E)-N′-(5-acetyl-2-hydroxybenzylidene)-4-chlorobenzohydrazide

The title compound was prepared from 5-acetyl-2-hydroxybenzaldehyde (500mg, 3.1 mmol) using a procedure similar to that described forPreparation 3. The product was obtained as a yellow coloured solid (923mg, 96. LRMS (ES⁺) m/z 317.2 [M+H

Preparation 18: 5-Acetyl-2-(4-chlorobenzoyl)benzaldehyde

The title compound was prepared from(E)-N′-(5-acetyl-2-hydroxybenzylidene)-4-chlorobenzohydrazide,(Preparation 17), (0.90 g, 2.8 mmol) and Pb(OAc)₄ (2.5 g, 5.7 mmol)using a procedure similar to that described for Preparation 5. LRMS(ES⁺) m/z 287.3 [M+H]⁺;

Preparation 19: 5-Acetyl-2-(4-chlorobenzoyl)benzoic acid

The title compound was prepared from5-acetyl-2-(4-chlorobenzoyl)benzaldehyde, Preparation 18, (690 mg, 2.4mmol) using a procedure similar to that described for Preparation 7. Theproduct was obtained as an off-white coloured solid (753 mg, 100%). LRMS(ES) m/z 301.2 [M−H]⁻;

Preparation 20:6-Acetyl-2-(4-chlorobenzyl)-3-(4-chlorophenyl)-3-hydroxyisoindolin-1-one

To a solution of 5-acetyl-2-(4-chlorobenzoyl)benzoic acid, Preparation19, (2.0 g, 6.6 mmol) in THF (8 mL) was added thionyl chloride (0.96 mL,13.2 mmol) and stirred at rt for 2 h before being concentrated in vacuo.The residue was dissolved in THF (8 mL) and 4-chlorobenzylamine (0.89mL, 7.3 mmol) and Hunig's base (1.3 mL, 7.3 mmol) were added and stirredat rt for 2 h before being diluted with EtOAc (8 mL). Washed with water(8 mL), brine (8 mL), dried (MgSO₄) and concentrated in vacuo.Purification (SP4, silica, EtOAc/petrol, 40%) gave Preparation 20 as ayellow solid (1.52 g, 54%). ¹H NMR (500 MHz, CDCl₃) δ 2.61 (3H, s, CH₃),3.21 (1H, br s, OH), 4.18 (1H, d, J=15.0 Hz, NCHH), 4.68 (1H, d, J=15.0Hz, NCHH), 7.14-7.26 (8H, m, H—Ar), 7.31 (1H, d, J=8.0 Hz, H-4), 8.07(1H, dd, J=1.6, 8.0 Hz, H-5), 8.26 (1H, d, J=1.6 Hz, H-7). LRMS (ES⁻)m/z 424.2 [M−H]⁻;

Preparation 21:6-Acetyl-2-(4-chlorobenzyl)-3-(4-chlorophenyl)-3-(2-hydroxyethoxy)isoindolin-1-one

The title compound was prepared in a similar fashion to Preparation 10,but using 0.8 mol. eq of InBr₃ and 20 mol. eq of ethylene glycol. ¹H NMR(500 MHz, CDCl₃) δ (ppm) 1.48-1.55 (m, 1H), 2.67 (s, 3H), 1.62 (s, 6H),2.80-2.92 (m, 2H), 3.32-3.52 (m, 2H), 4.11 (d, 1H), 4.67 (d, 1H),7.14-7.19 (m, 4H), 7.20-7.27 (m), 8.14 (dd, 1H), 8.43-8.46 (m). HMS(ES+)m/z 486.3 [M+H]⁺;

Preparation 22:6-Acetyl-3-(3-bromo-2,2-bis(hydroxymethyl)propoxy)-2-(4-chlorobenzyl)-3-(4-chlorophenyl)isoindolin-1-one

6-Acetyl-isoindolinone derivative (Preparation 20) (0.3 g, 0.704 mmol)in THF (5 mL) under a dried atmosphere of N₂ was added SOCl₂ (0.103 mL,1.41 mmol). The mixture was stirred for 2 hours at room temperaturebefore to be concentrated in vacuo. To the residue were added2-(bromomethyl)-2-(hydroxymethyl)-1,3-propanediol (0.42 g, 2.11 mmol)and anhydrous K₂CO₃ (0.194 g, 1.41 mmol), followed by THF (5 mL) and thereaction mixture was stirred overnight. After work-up, crude materialwas purified using chromatography on silica (Pet:EtOAc 1:0 to 0:1) togive a yellow solid Preparation 22 (0.186 g, 0.306 mmol. 1H NMR (500MHz, CDCl₃) δ (ppm) 2.67 (s, 3H, COCH₃), 2.78 (d, 1H, J=9.0 Hz, OCCHHC),3.00 (d, 1H, J=9.0 Hz, CCHHC), 3.45-3.65 (m, 6H, CCH₂Br, C(CH₂OH)₂),4.41 (d, 1H, J=15.1 Hz, NCHH), 4.45 (d, 1H, J=15.1 Hz, NCHH), 7.02-7.11(m, 4H, Ar—H), 7.13 (d, 2H, J=8.5 Hz, Ar—H), 7.18 (d, 2H, J=8.7 Hz,Ar—H), 7.27 (d, 1H, J=8.0 Hz, isoindolinone-H), 8.15 (dd, 1H, J=7.9, 1.6Hz, isoindolinone-H), 8.45 (d, 1H, J=1.2 Hz, isoindolinone-H; MS(ES+)m/z 456.4 [M+H]⁺;

Preparation 23:6-Acetyl-2-(4-chlorobenzyl)-3-(4-chlorophenyl)-3-((3-(hydroxymethyl)oxetan-3-yl)methoxy)isoindolin-1-one

Bromo-diol (Preparation 22) (0.215 g, 0.354 mmol) was dissolved in EtOH(10 mL). KOH (0.023 g, 0.407 mmol) was added and the mixture was heatedto 90° C. and stirred for 6 hours. Once back to room temperature, H₂O(10 mL) was added followed by introduction of an aqueous 1M solution ofHCL until pH ˜2-3. The mixture was extracted with EtOAc (3×20 mL) andthe combined organic phases were washed with brine, dried over MgSO₄,filtered and evaporated in vacuo. Crude material purified usingchromatography on silica (Pet:EtOAc 1:0 to 1:3) to give the desiredproduct as a white foamy solid Preparation 23 (0.104 g, 0198 mmol) in 56¹H NMR (500 MHz, CDCl₃) δ (ppm) 1.73 (bs, 1H, OH), 2.67 (s, 3H), 2.92(d, 1H), 3.05 (d, 1H), 3.67-3.77 (m, 2H), 4.22 (d, 1H), 4.24-4.29 (m,2H), 4.31 (d, 1H), 4.36 (d, 1H), 4.57 (d, 1H), 7.10 (d, 1H), 7.12-7.18(m, 4H, H), 7.19-7.24 (m, 3H), 8.15 (dd, 1H), 8.46 (d, 1H); MS(ES+) m/z[M+H]⁺; 456.1624.

Preparation 24:(R)-3-(4-Chlorophenyl)-2-((S)-1-(4-chlorophenyl)ethyl)-3-((2-(hydroxymethyl)allyl)oxy)-6-(prop-1-en-2-yl)isoindolin-1-one

3-(4-Chlorophenyl)-2-((S)-1-(4-chlorophenyl)ethyl)-3-hydroxy-6-(prop-1-en-2-yl)isoindolin-1-one,Preparation 16, (250 mg, 0.57 mmol), 2-methylene-1,3-propandiol (0.23mL, 2.85 mmol), InBr₃ (305 mg, 0.86 mmol) and DCE (5 mL). Purification(SP4, silica, EtOAc/petrol, 25%) gave Preparation 24 as a white glassysolid (88 mg, 30%). R_(f)=0.64 (silica, EtOAc/petrol. ¹H NMR (500 MHz,CDCl₃) δ 1.85 (3H, d, J=7.3 Hz, benzylic CH₃), 2.17 (3H, s, isopropeneCH₃), 3.59 (1H, d, J=12.2 Hz, -iso-OCHH), 3.81 (1H, d, J=12.2 Hz,-iso-OCHH), 4.16-4.23 (2H, m, CH₂OH), 4.40 (1H, q, J=7.3 Hz,H-benzylic), 5.17-5.18 (1H, m, H-isopropene), 5.21-5.24 (2H, m,side-chain alkene CH₂), 5.44-5.45 (1H, m, H-isopropene), 6.95-7.10 (9H,m, H—Ar), 7.59 (1H, dd, J=1.7, 7.9 Hz, H-5), 7.92 (1H, d, J=1.7 Hz,H-7). LRMS (ES⁺) m/z 508.4 [M+H]⁺.

Preparation 25a and 25b:6-Bromo-3-(4-chlorophenyl)-2-((S)-1-(4-chlorophenyl)ethyl)-3-hydroxyisoindolin-1-one

Starting from 5-bromo-2-(4-chlorobenzoyl)benzoic acid (Preparation 6)and (1S)-1-(4-chlorophenyl)ethan-1-amine the title compounds,Preparation 25a and 25b were prepared using procedures similar to thosedescribed for Preparation 9. Products obtained as off white solids.

25a (S,S): MS (ES+) 477.3 [M+H]⁺. R_(f)=0.73 (1:1 EtOAc/petrol);

25b (R,S): MS (ES+) 477.3 [M+H]⁺. R_(f)=0.64 (1:1 EtOAc/petrol

Preparations 26a and 26b:6-Bromo-3-(4-chlorophenyl)-2-((S)-1-(4-chlorophenyl)ethyl)-3-((1-hydroxymethyl)cyclopropyl)methoxy)isoindolin-1-one

Preparations 26a and 26b were prepared using procedures similar to thosedescribed for Preparation 12.

26a (S,S): MS (ES+) 460.2 [M−HOCH₂(c-Pr)CH₂O]⁺.): R_(f)=0.51 (2:3EtOAc/petrol);

26b (R,S): MS (ES+) 460.2 [M−HOCH₂(c-Pr)CH₂O, R_(f)=0.42 (2:3EtOAc/petrol);

Preparation 27:(R)-3-(4-Chlorophenyl)-2-((S)-1-(4-chlorophenyl)ethyl)-3-((1-(hydroxymethyl)cyclopropyl)methoxy)-6-(prop-1-en-2-yl)isoindolin-1-one

Starting from intermediate 26b (500 mg, 0.89 mmol), Preparation 27 wasprepared using similar procedures to those described for Preparation 13.MS (ES+) 522.5 [M+H]⁺.

Preparation 28:(R)-6-Acetyl-3-(4-chlorophenyl)-2-((S)-1-(4-chlorophenyl)ethyl)-3-((1-(hydroxymethyl)cyclopropyl)methoxy)isoindolin-1-one

Starting from Preparation 27, Preparation 28 was prepared using similarprocedures to those described for Preparation 15. MS (ES+) 524.5 [M+H]⁺.

Preparation 29:(R)-3-((1-(((tert-Butyldimethylsilyl)oxy)methyl)cyclopropyl)methoxy)-3-(4-chlorophenyl)-2-((S)-1-(4-chlorophenyl)ethyl)-6-(prop-1-en-2-yl)isoindolin-1-one

To a solution of(R)-3-(4-chlorophenyl)-2-((S)-1-(4-chlorophenyl)ethyl)-3-((1-(hydroxymethyl)cyclopropyl)methoxy)-6-(prop-1-en-2-yl)isoindolin-1-one,Preparation 27 (2.20 g, 4.21 mmol) in THF (50 mL) was added TBDMSCl(1.27 g, 8.42 mmol) and imidazole (860 mg, 12.6 mmol) and the mixtureheated at 85° C. for 5 h. The reaction was cooled to RT, extracted intoEtOAc (100 mL), washed with 0.3 M aqueous HCl (150 mL), water (150 mL),brine (150 mL), dried over MgSO₄ and concentrated under vacuum. MPLC(95:5 petrol to EtOAc then 99:1 petrol/EtOAc) gave the title compound,Preparation 29 as a colourless oil (1.83 g, 68%); MS (ES+) 422.3[M-(TBDMSOCH₂(c-Pr)CH₂O)]⁺.

Preparation 30:(3R)-3-((1-(((tert-Butyldimethylsilyl)oxy)methyl)cyclopropyl)methoxy)-3-(4-chlorophenyl)-2-((S)-1-(4-chlorophenyl)ethyl)-6-(2-methyloxiran-2-yl)isoindolin-1-one

At 0° C., to a solution of(R)-3-((1-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)methoxy)-3-(4-chlorophenyl)-2-((S)-1-(4-chlorophenyl)ethyl)-6-(prop-1-en-2-yl)isoindolin-1-one,Preparation 29 (500 mg, 0.79 mmol) in DCM (43 mL) was added portionwisemCPBA (271 mg, 1.57 mmol) and the resulting solution stirred at RT for18 h. The reaction was quenched by addition of saturated aqueous NaHCO₃(25 mL) and stirred at RT for 30 min. The organic layer was separated,washed with brine (40 mL), dried over MgSO₄ and concentrated undervacuum. The crude product, Preparation 30 was obtained as a colourlessoil and carried forward to the next step without purification (708 mg);MS (ES+) 436.3 [M-(TBDMSOCH₂(c-Pr)CH₂O)]⁺.

Preparation 31:(3R)-3-((1-(((tert-Butyldimethylsilyl)oxy)methyl)cyclopropyl)methoxy)-3-(4-chlorophenyl)-2-((S)-1-(4-chlorophenyl)ethyl)-6-(2-hydroxy-1-methoxypropan-2-yl)isoindolin-1-one

To a solution of sodium (249 mg, 10.8 mmol) in MeOH (1.5 mL) was addeddropwise a solution of(3R)-3-((1-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)methoxy)-3-(4-chlorophenyl)-2-((S)-1-(4-chlorophenyl)ethyl)-6-(2-methyloxiran-2-yl)isoindolin-1-one,Preparation 30 (708 mg, 1.08 mmol) in MeOH (1.5 mL) and the resultingsolution stirred at RT for 18 h then at 65° C. for 5 h. The reaction wascooled to RT, NaOMe (292 mg, 5.4 mmol) was added and the mixture heatedat 65° C. for 2 h then cooled to RT. The reaction was quenched byaddition of water (100 mL), neutralised with aqueous 1.0 M HCl solution,extracted into EtOAc (2×100 mL), washed with brine (100 mL), dried overMgSO₄ and concentrated under vacuum. MPLC (3:2 petrol/EtOAc) gave thetitle compound, Preparation 31 as a colourless oil as adiastereoisomeric mixture (151 mg, 20; MS (ES+) 468.3[M-(TBDMSOCH₂(c-Pr)CH₂O)]⁺.

Preparation 32:3-((1-(((tert-Butyldimethylsilyl)oxy)methyl)cyclopropyl)methoxy)-2-(4-chlorobenzyl)-3-(4-chlorophenyl)-6-(prop-1-en-2-yl)isoindolin-1-one

To a solution of2-(4-chlorobenzyl)-3-(4-chlorophenyl)-3-((1-(hydroxymethyl)cyclopropyl)methoxy)-6-(prop-1-en-2-yl)isoindolin-1-one,Preparation 13 (2.73 g, 5.37 mmol) in THF (68 mL) was added TBDMSCl(1.62 g, 10.7 mmol) and imidazole (1.10 g, 16.1 mmol) and the resultingsuspension heated at 85° C. for 5 h then cooled to RT. The mixture wasdiluted with EtOAc (150 mL), washed with aqueous 0.3 M HCl (150 mL),water (150 mL), brine (150 mL) and dried over MgSO₄. Purification byMPLC (100% petrol to 95:5 petrol/EtOAc) gave the title compound,Preparation 32 as a colourless oil (1.12 g, 34%); λ_(max) (EtOH/nm) 214;IR (cm⁻¹) 2928, 2855, 1704 (C═O), 1433; ¹H NMR (500 MHz, CDCl₃) δ −0.11(3H, s, SiCH₃), −0.09 (3H, s, SiCH₃), 0.00-0.03 (2H, m, 2×c-PrH),0.25-0.27 (2H, m, 2×c-PrH), 0.73 (9H, s, SiC(CH₃)₃), 2.08 (3H, m, CH₃),2.52 (1H, d, J=9.2 Hz, CHH′), 2.80 (1H, d, J=9.2 Hz, CHH′), 3.27 (1H, d,J=10.3 Hz, C′HH′), 3.56 (1H, d, J=10.3 Hz, C′HH′), 4.22 (1H, d, J=14.7Hz, NCHH′), 4.30 (1H, d, J=14.7 Hz, NCHH′), 5.08 (1H, m, alkene-CH),5.35 (1H, s, alkene-CH′), 6.94 (1H, d, J=8.0 Hz, ArH), 6.95-7.01 (4H, m,4×ArH), 7.05-7.09 (4H, m, 4×ArH), 7.48 (1H, dd, J=1.7 and 8.0 Hz, ArH),7.86 (1H, d, J=1.7 Hz, ArH); ¹³C (125 MHz, CDCl₃) δ −5.2, −5.3, 7.9,8.1, 18.3, 12.9, 25.9, 42.2, 65.9, 66.1, 94.3, 114.3, 120.4, 122.8,128.0, 128.2, 128.4, 130.1, 130.5, 131.6, 133.0, 134.3, 136.0, 137.4,142.1, 168.3; MS (ES+) 408.3 [M-(TBDMSOCH₂(c-Pr)CH₂O)]⁺.

Preparation 33:3-((1-(((tert-Butyldimethylsilyl)oxy)methyl)cyclopropyl)methoxy)-2-(4-chlorobenzyl)-3-(4-chlorophenyl)-6-(2-methyloxiran-2-yl)isoindolin-1-one

At 0° C., to a solution of3-((1-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)methoxy)-2-(4-chlorobenzyl)-3-(4-chlorophenyl)-6-(prop-1-en-2-yl)isoindolin-1-one,Preparation 32 (640 mg, 1.03 mmol) in DCM (50 mL) was added mCPBA (355mg, 2.05 mmol) and the resulting solution stirred at RT for 18 h. Thereaction was quenched by addition of saturated aqueous NaHCO₃ (50 mL)and stirred vigorously for 4 h. The organic layer was separated, washedwith brine (50 mL), dried over MgSO₄ and concentrated under vacuum. Thecrude product, Preparation 33 was carried forward to the next stepwithout purification (650 mg). MS (ES+) 422.3[M-(TBDMSOCH₂(c-Pr)CH₂O)]⁺.

Preparation 34:3-((1-(((tert-Butyldimethylsilyl)oxy)methyl)cyclopropyl)methoxy)-2-(4-chlorobenzyl)-3-(4-chlorophenyl)-6-(1-(dimethylamino)-2-hydroxypropan-2-yl)isoindolin-1-one

In a sealed microwave vial, to a solution of3-((1-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)methoxy)-2-(4-chlorobenzyl)-3-(4-chlorophenyl)-6-(2-methyloxiran-2-yl)isoindolin-1-one,Preparation 33 (1.08 g, 1.69 mmol) in MeOH (3.04 mL) was addeddimethylamine (8.45 mL, 16.9 mmol, 2.0 M in MeOH) and the resultingsolution heated at 60° C. for 4 h then cooled to RT. The reaction wasdiluted with water (50 mL), extracted into EtOAc (2×50 mL), washed withbrine (100 mL), dried over MgSO₄ and concentrated under vacuum. Purifiedby Biotage using 0-30% MeOH in EtOAc as the eluent gave the titlecompound as a colourless oil (407 mg, 35%). 1H NMR (500 MHz, CDCl₃)−0.02 (3H, m), 0.00 (3H, s), 0.03-0.12 (2H, m), 0.34-0.35 (2H, m),0.83-0.84 (9H, m), 1.51 (3H, s), 2.19 (6H, s), 2.61-2.64 (1H, m),2.76-2.83 (3H, m), 3.35-3.39 (1H, m), 3.63-3.67 (1H, m), 4.30-4.40 (2H,m), 7.05-7.10 (5H, m), 7.15 (4H, s), 7.68-7.71 (1H, m), 7.91-7.92 (1H,m).

Preparation 35: (S)-Ethyl 3-amino-3-(4-chlorophenyl)propanoatehydrochloride

At 0° C., to a solution of s-beta-(p-chlorophenyl)alanine (1.00 g, 5.0mmol) in EtOH (10 mL) was added dropwise SOCl₂ and the resultingsolution heated at 78° C. for 1.5 h. The solution was cooled to RT andconcentrated under vacuum to give the title compound, Preparation 35 asa white solid (1.31 g, 99%); ¹H NMR (500 MHz, DMSO) δ 1.08 (3H, t, J=7.1Hz, CH₃), 3.02 (1H, dd, J=9.5 and 16.1 Hz, CHH′C═O), 3.24 (1H, dd, J=5.4and 16.1 Hz, CHH′C═O), 3.96-4.01 (2H, m, OCH₂), 4.59 (1H, dd, J=5.4 and9.5 Hz, NH₂CH), 7.49 (2H, d, J=8.5 Hz, 2×ArH), 7.62 (2H, d, J=8.5 Hz,2×ArH), 8.91 (3H, s br)

Preparation 36; (3S)-Ethyl3-(5-bromo-1-(4-chlorophenyl)-1-hydroxy-3-oxoisoindolin-2-yl)-3-(4-chlorophenyl)propanoate

Starting from (S)-Ethyl 3-amino-3-(4-chlorophenyl)propanoatehydrochloride, preparation 35 was prepared using similar procedures tothose described for Preparation 9. Product was obtained as adiastereoisomeric mixture. MS (ES+) 546.2 [M−H]⁻.

Preparation 37a and 37b: (3S)-Ethyl3-(5-bromo-1-(4-chlorophenyl)-1-((1-(hydroxymethyl)cyclopropyl)methoxy)-3-oxoisoindolin-2-yl)-3-(4-chlorophenyl)propanoate

Starting from3-(5-bromo-1-(4-chlorophenyl)-1-hydroxy-3-oxoisoindolin-2-yl)-3-(4-chlorophenyl)propanoatePreparation 37a and 37b were prepared using similar procedures to thosedescribed for Preparation 12. The two products were isolated by SiO₂chromatography.

37a (S,S): R_(f)=0.67 (1:1 EtOAc/petrol); MS (ES+) 532.2[M−HOCH₂(c-Pr)CH₂O]⁺.

37b (S,R): R_(f)=0.52 (1:1 EtOAc/petrol); MS (ES+) 530.3[M−HOCH₂(c-Pr)CH₂O]⁺.

Preparation 38: (S)-Ethyl3-(4-chlorophenyl)-3-((R)-1-(4-chlorophenyl)-1-((1-(hydroxymethyl)cyclopropyl)methoxy)-3-oxo-5-(prop-1-en-2-yl)isoindolin-2-yl)propanoate

Starting from preparation 37b, Preparation 38 was prepared using similarprocedures to those described for Preparation 13. MS (ES+) 492.4[M−HOCH₂(c-Pr)CH₂O]⁺.

Preparation 39: (S)-Ethyl3-((R)-5-acetyl-1-(4-chlorophenyl)-1-((1-(hydroxymethyl)cyclopropyl)methoxy)-3-oxoisoindolin-2-yl)-3-(4-chlorophenyl)propanoate

Starting from Preparation 38, Preparation 39 was prepared using similarprocedures to those described for Preparation 15. MS (ES+) 494.3[M−HOCH₂(c-Pr)CH₂O]⁺.

Preparation 40:(S)-3-((R)-5-Acetyl-1-(4-chlorophenyl)-1-((1-(hydroxymethyl)cyclopropyl)methoxy)-3-oxoisoindolin-2-yl)-3-(4-chlorophenyl)propanoicacid

To a solution of (S)-ethyl3-((R)-5-acetyl-1-(4-chlorophenyl)-1-((1-(hydroxymethyl)cyclopropyl)methoxy)-3-oxoisoindolin-2-yl)-3-(4-chlorophenyl)propanoate,Preparation 39 (130 mg, 0.22 mmol) in THF/water (1.9 mL/3.0 mL) wasadded LiOH.H₂O (183 mg, 4.36 mmol) and the resulting yellow solutionheated at 60° C. for 3 h then cooled to RT. The solution was acidifiedto pH 5 with aqueous 1.0 M HCl, extracted with EtOAc (3×25 mL), washedwith brine (50 mL), dried over MgSO₄ and concentrated under vacuum. MPLC(1:1 petrol/EtOAc (0.1% AcOH) to 100% EtOAc (0.1% AcOH)) gave the titlecompound, Preparation 40 as a white solid (85 mg, 68%); MS (ES+) 566.2[M−H]⁻.

Preparation 41:6-Acetyl-2-(4-chlorobenzyl)-3-(4-chlorophenyl)-3-(3-hydroxy-3-methylbutoxy)isoindolin-1-one

Starting from6-acetyl-2-(4-chlorobenzyl)-3-(4-chlorophenyl)-3-hydroxyisoindolin-1-one,Preparation 41 was prepared using similar procedure to those describedin Preparation 12.

Preparation 42: 4-[(Triisopropylsilanyl)-ethynyl]-benzylamine

Step 1: (4-Chloro-benzyl)-carbamic acid tert-butyl ester

4-Chlorobenzylamine (10.5 mL, 86 mmol) was added to a mixture ofAmberlyst 15 resin (1.8 g) and di-tert-butyl dicarbonate (18.5 g, 84.7mmol) and the reaction mixture was stirred at room temperature for 3hours. The crude mixture was diluted with DCM (200 mL) and the catalystwas removed by filtration. The solvent was removed in vacuo to give thedesired product as a white solid (18.9 g). MS: [M-C₄H₉]⁺=186. ¹H NMR(400 MHz, CDCl3): 7.38-7.30 (2H, m), 7.23 (2H, d), 4.87 (1H, s), 4.29(2H, s), 1.48 (9H, s).

Step 2: {4-[(Triisopropylsilanyl)-ethynyl]-benzyl}-carbamic acidtert-butyl ester

Ethynyl-triisopropyl-silane (13.4 mL, 94.1 mmol) was added to asuspension of (4-chloro-benzyl)-carbamic acid tert-butyl ester (18.9 g,78.4 mmol), PdCl₂(CH₃CN)₂ (202 mg, 0.78 mmol), XPhos (1.1 g, 2.3 mmol)and Cs₂C03 (53.6 g, 164.6 mmol) in MeCN (170 mL) and the reactionmixture was stirred under N₂ at 110° C. for 20 hours. The reaction wasthen cooled to room temperature, quenched with water (300 mL) andextracted with EtOAc (2×300 mL). The organic phases were collected,dried over Na₂SO₄. The reaction was then cooled to room temperature,quenched with water (300 mL) and extracted with EtOAc (2×300 mL). Theorganic phases were collected, dried over Na₂SO₄, filtered andconcentrated in vacuo. The crude material was columned (gradient 0-20%EtOAc in Petrol) to give 15.7 g of a yellow oil. 1H NMR (400 MHz,CDCl3): 7.45 (2H, d), 7.23 (2H, d), 4.83 (1H, s), 4.32 (2H, s), 1.48(9H, s), 1.20-1.11 (21H, m).

Step 3: 4-[(Triisopropylsilanyl)-ethynyl]-benzylamine

TFA (25 mL, 326 mmol) was added to a solution of{4-[(Triisopropylsilanyl)-ethynyl]-benzyl}-carbamic acid tert-butylester (15.6 g, 40.3 mmol) in DCM (50 mL). The reaction was stirred for16 hours at room temperature and then quenched with water (30 mL) and 2NNaOH until the solution reached pH=11. The product was extracted withDCM (3×). The organic phases were collected, dried over Na₂SO₄, filteredand concentrated in vacuo to give the desired product (12.5 g) as anorange oil. 1H NMR (400 MHz, CDCl3): 7.46 (2H, d), 7.31-7.24 (2H, m),3.87 (2H, s), 1.94 (2H, s), 1.15 (21H, s).

Preparation 43: 4-Chloro-2-(methylthio)phenyl)methanamine

To a solution of 4-chloro-2-(methylthio)benzonitrile (500 mg, 2.72 mmol)in dry THF (10 mL) was added slowly borane-THF complex (1M in THF, 13.6mL, 13.6 mmol) at 0° C. before refluxing for 1 h. After cooling, 1 M HClin MeOH (10 mL) was added slowly with ice cooling. The solvent wasremoved by concentration in vacuo before water (0.61 mmol/mL tobenzonitrile) was added, then washed by Et₂O (0.61 mmol/mL tobenzonitrile) before basifying with 2 M NaOH solution to pH 12. Et₂O(0.61 mmol/mL to benzonitrile) was added and the mixture was washed withwater (3×0.61 mmol/mL to benzonitrile) and brine (0.4 mol/mL tobenzonitrile). The organic layer was dried (MgSO₄) and concentrated invacuo to give the product as a yellow oil (400 mg, 78%). LCMS (ESI⁺)m/z=171.1 [M-NH₂]⁺.

Preparation 44:(3R)-6-Acetyl-2-[(4-chloro-2-methanesulfonylphenyl)methyl]-3-(4-chlorophenyl)-4-fluoro-3-[(3R)-oxolan-3-yloxy]-2,3-dihydro-1H-isoindol-1-one

The title compound was prepared using a similar method to that describedin Example 41, Step 1 and 2; using (3R)-hydroxy-tetrahydrofuran insteadof cyclopropane-1,1-dimethanol. The 3(R) isomer was isolated as theslower running fraction from Step 1, using preparative chiral HPLC.MS(ES+) m/z 630 [M+H]⁺.

Preparation 45: Ethyl(3S)-3-[(1R)-5-acetyl-1-(4-chlorophenyl)-7-fluoro-3-oxo-1-[(3S)-oxolan-3-yloxy]-2,3-dihydro-1H-isoindol-2-yl]-3-(4-chlorophenyl)propanoate

The title compound was prepared in a similar way to Preparation 44, butusing ethyl (3S)-3-amino-3-(4-chlorophenyl)propanoate hydrochloride(Preparation 35) instead of(4-chloro-2-(methylsulfonyl)phenyl)methanamine and(3S)-hydroxy-tetrahydrofuran instead of (3R)-hydroxy-tetrahydrofuran.MS(ES+) m/z 598 [M−H]⁻

Preparation 46:2-(4-Chlorobenzoyl)-3-fluoro-5-(1-hydroxy-1-methyl-ethyl)benzoic acid

The title compound was prepared in a similar fashion to Example 73 and74, Step 1; but using acetone instead of1-methyl-1H-pyrazole-4-carboxaldehyde. MS: [M+H]⁺=337.

Preparation 47: (2-(Aminomethyl)-5-chlorophenyl)dimethylphosphine oxide

Step 1: 4-Chloro-2-(dimethylphosphoryl)benzonitrile

To a round bottomed flask was added 4-chloro-2-iodobenzonitrile (2.5 g,9.50 mmol), dimethylphosphine oxide (1.12 g, 14.30 mmol), Pd₂(dba)₃ (435mg, 0.48 mmol), Xantphos (550 mg, 0.95 mmol) and the flask was flushedwith N₂. The solids were taken up in dioxane (25 mL), triethylamineadded (2.10 g, 20.9 mmol) and the reaction was stirred at roomtemperature for 2 h. To the reaction was added H₂O (50 mL) and theaqueous was extracted with EtOAc (2×100 mL). The combined organics weredried (MgSO₄), filtered and concentrated in vacuo. The residue waspurified on a 50 g SNAP column eluting with MeOH in DCM (0 to 10%) togive the title compound (1.07 g at 80% purity). ¹H NMR (400 MHz, CDCl₃)8.33-8.29 (1H, m), 7.76-7.73 (1H, m), 7.65-7.62 (1H, m), 1.96 (6H, d);

Step 2: (2-(Aminomethyl)-5-chlorophenyl)dimethylphosphine oxide

To a THF solution (10 mL) of 4-chloro-2-(dimethylphosphoryl)benzonitrile(960 mg, 4.50 mmol), under N₂, was added BH₃.THF (23 mL, 23.00 mmol, 1MTHF) and the reaction was stirred for 1 h. The reaction was quenched bythe cautious addition of MeOH (10 mL). The solution was concentrated invacuo., re-dissolved in MeOH and loaded on to a 10 g SCXII cartridge.The cartridge was sequentially flushed with MeOH (3 column volumes) andthen 2M NH₃ MeOH (3 column volumes). The ammonia wash was concentratedin vacuo. to give the title compound (770 mg). ¹H NMR (400 MHz, CDCl₃)7.46-7.41 (3H, m), 4.14 (2H, s), 1.83 (6H, d).

Preparation 48:2-(4-Chlorobenzoyl)-3-fluoro-5-(tetrahydro-2H-pyran-4-carbonyl)benzoicacid

Steps 1 was performed using a procedure similar to that described inExamples 73 and 74; step 1, but using tetrahydro-2H-pyran-4-carbaldehydeinstead of 1-methyl-1H-pyrazole-4-carboxaldehyde. Also, Bu₂Mg was usedin place of methylmagnesium chloride. MS: [M+H]⁺=393.

Step 2:2-(4-Chlorobenzoyl)-3-fluoro-5-(tetrahydro-2H-pyran-4-carbonyl)benzoicacid

2-(4-Chlorobenzoyl)-3-fluoro-5-(hydroxy(tetrahydro-2H-pyran-4-yl)methyl)benzoicacid (17.4 g, 44.4 mmol) was stirred in DCM (400 mL) at RT then TEMPO(0.69 g, 4.44 mmol) and tetra-n-butylammonium chloride (5.72 g, 17.8mmol) were added followed by OXONE®, monopersulfate compound (30 g, 97.7mmol). The reaction was allowed to stir at RT for 18 h. TEMPO (0.69 g,4.44 mmol) was added and the reaction was allowed to stir at RT for anadditional 48 h. The solids were removed by filtration and the filtercake was washed with DCM (2×100 mL). The combined filtrates wereconcentrated under reduced pressure and the resulting residue dissolvedin EtOAc (500 mL). The combined organic portions were washed with 2M HClaqueous solution (2×500 mL) and brine (200 mL), dried (MgSO₄), filteredand concentrated to afford the title compound as a pale yellow foam (16g, 92% yield). MS: [M−H]⁺=389.

Preparation 49: 4-[(1R)-1-Amino-2-(prop-2-en-1-yloxy)ethyl]benzonitrile

Step 1:N-[(1R)-1-(4-Cyanophenyl)-2-hydroxyethyl]-2,2,2-trifluoroacetamide

TFAA (3.6 mL, 25.2 mmol) was added to a solution of4-[(1R)-1-amino-2-hydroxyethyl]benzonitrile (5.0 g, 25.2 mmol) in DCM(100 mL) containing TEA (10.9 mL, 75.6 mmol) and the solution wasstirred for 10 min at room temperature. The reaction was partitionedbetween DCM and 2N HCl. The aqueous phase was extracted with DCM (2×)and EtOAc (2×). The organic phases were collected, dried over MgSO₄,filtered and concentrated in vacuo to give the desired product as awhite solid (4.8 g, 74% yield). LCMS: [M−H]⁻=257.

Step 2:N-[(1R)-1-(4-Cyanophenyl)-2-(prop-2-en-1-yloxy)ethyl]-2,2,2-trifluoroacetamide

NaH (60% disp. in oil, 1.5 g, 36.9 mmol) was added in portions to asolution ofN-[(1R)-1-(4-cyanophenyl)-2-hydroxyethyl]-2,2,2-trifluoroacetamide (4.76g, 18.4 mmoL) in DMF (15 mL) at 0° C. under inert atmosphere and theresulting mixture was then stirred for 10 min at room temperature.3-iodoprop-1-ene (1.7 mL, 18.4 mmol) was then added dropwise, thereaction was stirred for 10 min at room temperature and then quenchedwith water. The product was extracted with EtOAc (3×), the organic phasewas washed 3× with brine and the solvent was removed in vacuo. The crudematerial was purified by flash chromatography on silica gel (gradient0-30% EtOAc in petrol) to give the title compound as a colourless liquid(3.5 g, 64% yield). LCMS: [M+H]⁺=299.

Step 3: 4-[(1R)-1-Amino-2-(prop-2-en-1-yloxy)ethyl]benzonitrile

2N NaOH (10 mL) was added to a solution ofN-[(1R)-1-(4-cyanophenyl)-2-(prop-2-en-1-yloxy)ethyl]-2,2,2-trifluoroacetamide(3.5 g, 11.7 mmol) in MeOH (10 mL). The reaction was stirred for 16hours at room temperature after which time 4 mL of 2N NaOH were added tothe mixture and stirring was continued for further 2 hours at 45° C. Thesolvent was removed in vacuo and the residue was partitioned betweenEtOAc and NaHCO₃. The organic phase was dried over MgSO₄, filtered andconcentrated in vacuo to give 2.3 g (96% yield) of the desired compoundas a pale yellow oil. LCMS: [M+H]⁺=203.

Preparation 50:2-(4-Chlorobenzoyl)-3-fluoro-5-(1-methyl-1H-imidazole-4-carbonyl)benzoicacid

Step 1:2-(4-Chlorobenzoyl)-3-fluoro-5-(hydroxy(1-methyl-1H-imidazol-4-yl)methyl)benzoicacid

A 10 litre round bottomed flask fitted with an overhead stirrer with alarge paddle was charged with5-bromo-2-(4-chlorobenzoyl)-3-fluorobenzoic acid (178.25 g; 0.5 mol) andanhydrous THF (2610 mL) added. This solution was cooled to −5° C.<T<0°C. and a solution of 3 M methyl magnesium chloride in THF (183 mL; 0.55mol) was added dropwise at such a rate that the internal temperatureremained below 0° C. On complete addition the mixture was stirred at 0°C. for 15 minutes and then cooled to −78° C. A solution of 2.5 Mn-butyllithium in hexanes (259 mL; 0.647 mol) was added drop-wise atsuch a rate so that the internal temperature remained below −70° C. Thereaction deepened in colour and thickened considerably ending up with asludge like consistency. On complete addition the mixture was stirred at−78° C. for 30 minutes prior to the addition of a solution of1-methyl-1H-imidazole-4-carbaldehyde (71.3 g; 0.648 mol) in anhydrousTHF (500 mL) dropwise at such a rate so that the internal temperatureremained below −70° C. On complete addition the mixture was stirred at−78° C. for 30 minutes, the cooling bath removed and the mixture allowedto reach room temperature. The mixture was quenched with 1 M HCl, the pHadjusted to 7 and the whole evaporated under reduced pressure Theresidue was divided into 4 equal portions and each portionchromatographed on silica gel (300 g) eluting with 0-30% MeOH in DCMgradient to afford the title compound as a yellow solid (151 g; 78%). MS[M+H]⁺=389

Step 2:2-(4-Chlorobenzoyl)-3-fluoro-5-(1-methyl-1H-imidazole-4-carbonyl)benzoicacid

To a stirred mixture of2-(4-chlorobenzoyl)-3-fluoro-5-(hydroxy(1-methyl-1H-imidazol-4-yl)methyl)benzoicacid (24.6 g; 63.4 mmol) in 1,4-dioxane (600 mL) was added activatedmanganese dioxide (55 g; 634 mmol) and the mixture heated at 110° C. for1 h. LCMS indicated complete reaction. The reaction was cooled, filteredthrough celite and GFA filter paper, washed with MeOH. The filtrate andwashings were combined and evaporated under reduced pressure to afford adark solid (24 g). MS [M+H]⁺=387.

Preparation 51: 3-((Allyloxy)methyl)-4-(aminomethyl)benzonitrilehydrochloride (4)

Step 1: tert-ButylN-[(2-bromo-4-cyano-phenyl)methyl]-N-tert-butoxycarbonyl-carbamate (2)

3-Bromo-4-(bromomethyl)benzonitrile (1) (8 g, 29.1 mmol), was dissolvedin THF (80 mL) and DMF (80 mL) and the solution was stirred at roomtemperature under a nitrogen atmosphere. Di-tert-butylimino carboxylate(9.48 g, 43.6 mmol) and potassium carbonate (6.0 g, 43.6 mmol) wereadded and the reaction was heated at 100° C. overnight. The mixture wasdiluted with EtOAc (250 mL) and water (250 mL). The organic phase wascollected and the aqueous phase was extracted with EtOAc (250 mL). Thecombined organic extracts were washed with brine (120 mL), dried(MgSO₄), filtered, and evaporated to dryness. The crude product waspurified by trituration with the minimal amount of methanol (˜20 mL) andthe solid was collected via filtration to give the desired product (10.3g, 86%) as a white solid. ¹H NMR (400 MHz, CDCl₃): 7.84 (1H, d), 7.59(1H, dd), 7.23 (1H, d), 4.88 (2H, s), 1.46 (18H, s)

Step 2: tert-ButylN-[[2-(Allyloxymethyl)-4-cyano-phenyl]methyl]-N-tert-butoxycarbonyl-carbamate(3)

tert-ButylN-[(2-bromo-4-cyano-phenyl)methyl]-N-tert-butoxycarbonyl-carbamate (2)(5 g, 12.1 mmol), RuPhos (0.569 g, 1.21 mmol), potassium[(allyloxy)methyl]trifluoroborane 2.6 g, 14.6 mmol) and cesium carbonate(11.9 g, 36.1 mmoL) were dissolved in dioxane (90 mL) and water (10 mL).The mixture was purged with nitrogen for 5 minutes and then palladiumacetate (136 mg, 0.61 mmol) was added. The mixture was purged withnitrogen for a further 5 minutes and then heated at 100° C. for 24hours. The mixture was concentrated under reduced pressure and theresulting residue was partitioned between EtOAc (150 mL) and water (150mL). The organic layer was collected and the aqueous phase was extractedwith more EtOAc (150 mL). The combined organic extracts were passedthrough a hydrophobic frit, and evaporated under reduced pressure togive a crude product which was purified by silica column chromatography(gradient elution 0 to 20% EtOAc in iso-Hex), to give the pure product(3.0 g, 53%) as a yellow oil. ¹H NMR (400 MHz, CDCl₃): P 7.68 (1H, d),7.59-7.56 (1H, m), 7.29 (1H, d), 5.99-5.89 (1H, m), 5.35-5.22 (2H, m),4.86 (2H, s), 4.56 (2H, s), 4.07-4.04 (2H, m), 1.44 (18H, s), 0.95-0.82(1H, m)

Step 3: 3-((Allyloxy)methyl)-4-(aminomethyl)benzonitrile hydrochloride(4)

tert-ButylN-[[2-(allyloxymethyl)-4-cyano-phenyl]methyl]-N-tert-butoxycarbonyl-carbamate(3) (2.6 g, 6.46 mmol) was dissolved in DCM (83 mL) and 4N HCl indioxane (28.6 mL) was added. The mixture was stirred at room temperaturefor 4 hours. The solvents were removed under vacuum and any remainingsolvent traces were removed via co-evaporation from chloroform. Thedesired product (1.6 g) was isolated as a white solid and was deemed tobe sufficiently pure for subsequent steps. ¹H NMR (400 MHz, DMSO):8.51-8.51 (3H, m), 7.93 (1H, dd), 7.88 (1H, d), 7.71 (1H, d), 6.02-5.92(1H, m), 5.33 (1H, ddd), 5.22 (1H, dd), 4.65 (2H, s), 4.16 (2H, s), 4.06(2H, d);

Preparation 52:(S)-2-(4-chlorobenzoyl)-3-fluoro-5-(1-hydroxy-1-(tetrahydro-2H-pyran-4-yl)propyl)benzoicacid

Step 1:2-(4-Chlorobenzoyl)-3-fluoro-5-(1-hydroxy-1-(tetrahydro-2H-pyran-4-yl)propyl)benzoicacid

To 50 mL of THF at −50° C. under nitrogen atmosphere was addeddiethylzinc (62 mL, 1M solution in hexanes, 62.0 mmol) and ethyl lithium(36 mL, 1.72 M solution in dibutyl ether, 62.0 mmol). The mixture wasstirred at −50° C. for 1 h and then2-(4-chlorobenzoyl)-3-fluoro-5-(tetrahydro-2H-pyran-4-carbonyl)benzoicacid (Preparation 48, 9.7 g, 24.0 mmol) was added as a THF (100 mL)solution. The mixture turned dark orange immediately and the internaltemperature reached −22° C. The mixture was stirred at −50° C. for 20min before being quenched by slow addition of 2N HCl (500 mL) (Caution).After stirring for 1 h, the pH was adjusted to 1-2 with 2M HCl and theaqueous was extracted with ethyl acetate (200 mL), washed with 2M HCl(75 mL), dried over magnesium sulfate, filtered and concentrated. Thecrude product was purified by silica column chromatography (gradientelution 0 to 100% EtOAc in iso-hexane) to give the title compound (9.03g, 90%) as a colourless foam. MS: [M+H]⁺=421

Step 2: Methyl(S)-2-(4-chlorobenzoyl)-3-fluoro-5-(1-hydroxy-1-(tetrahydro-2H-pyran-4-yl)propyl)benzoate

To a round bottom flask containing crude2-(4-chlorobenzoyl)-3-fluoro-5-(1-hydroxy-1-(tetrahydro-2H-pyran-4-yl)propyl)benzoicacid (6.32 g, 15 mmol), K₂CO₃ (2.69 g, 19 mmol) and DMF (50 mL) wasadded methyl iodide (0.934 mL, 16 mmol). The reaction was stirred for1.5 h at room temperature, after which point LCMS showed completeconversion to the desired product. The mixture was concentrated underreduced pressure and the residue dissolved in ethyl acetate (150 mL) andwashed with water (100 mL), then a 4% aqueous LiCl solution (2×100 mL).The organic layer was dried over magnesium sulfate, filtered andconcentrated to give a pale yellow foam. The enantiomers were separatedusing chiral SFC to give the title compound (8.1 g) as a colourlesssolid.

Methyl(S)-2-(4-chlorobenzoyl)-3-fluoro-5-(1-hydroxy-1-(tetrahydro-2H-pyran-4-yl)propyl)benzoate:Fast running isomer MS: [M+H]⁺=435. [α]_(D) ²⁰=−1.83 (c 1.0, MeOH).

Methyl(R)-2-(4-chlorobenzoyl)-3-fluoro-5-(1-hydroxy-1-(tetrahydro-2H-pyran-4-yl)propyl)benzoate:Slow running isomer MS: [M+H]⁺=435. [α]_(D) ²⁰=+1.48 (c 1.0, MeOH).

Step 3:(S)-2-(4-Chlorobenzoyl)-3-fluoro-5-(1-hydroxy-1-(tetrahydro-2H-pyran-4-yl)propyl)benzoicacid

Methyl(S)-2-(4-chlorobenzoyl)-3-fluoro-5-(1-hydroxy-1-(tetrahydro-2H-pyran-4-yl)propyl)benzoate(8.2 g, 18.86 mmol) was dissolved in THF (250 mL), methanol (30 mL) andwater (50 mL). Anhydrous LiOH (2.26 g, 94.3 mmol) was added and themixture was stirred at room temperature for 2 h. The resultant solutionwas concentrated to approximately 60 mL volume, diluted with water (500mL) and washed with diethyl ether (400 mL). The aqueous layer was thenacidified with 2N HCl and extracted with DCM (3×200 mL). Combinedextracts were dried (MgSO₄) and evaporated to afford the title compound(8.1 g, quant.) as a colourless foam. ¹H NMR (400 MHz, CDCl₃) 7.86 (1H,s), 7.71 (2H, d), 7.49-7.41 (3H, m), 4.05 (1H, dd), 3.98-3.93 (1H, m),3.43-3.28 (2H, m), 1.97-1.89 (2H, m), 1.77-1.74 (1H, m), 1.52-1.40 (2H,m), 1.20-1.13 (1H, m), 0.75 (3H, dd), OH and COOH not observed. MS:[M−H⁺]⁻=419. [α]_(D) ²⁰=−2.3 (c 1.0, MeOH).

Preparation 52b:(R)-2-(4-chlorobenzoyl)-3-fluoro-5-(1-hydroxy-1-(tetrahydro-2H-pyran-4-yl)propyl)benzoicacid

The title compound was prepared in a similar fashion to Example 52, butusing(R)-2-(4-chlorobenzoyl)-3-fluoro-5-(1-hydroxy-1-(tetrahydro-2H-pyran-4-yl)propyl)benzoatein Step 3. MS: [M−H⁺]⁻=419. [α]_(D) ²⁰=+1.8 (c 10, MeOH).

Preparation 53:2-(4-chlorobenzoyl)-3-fluoro-5-(4-fluorotetrahydro-2H-pyran-4-carbonyl)benzoicacid

Step 1: Ethyl2-(4-chlorobenzoyl)-3-fluoro-5-(tetrahydro-2H-pyran-4-carbonyl)benzoate

To a stirred solution of2-(4-chlorobenzoyl)-3-fluoro-5-(tetrahydro-2H-pyran-4-carbonyl)benzoicacid (Preparation 48, 100 g, 258 mmol) in DMF (800 mL) was addedpotassium carbonate (54.8 g, 396 mmol) followed by iodoethane (26.8 mL,334 mmol). The mixture was stirred for 18 h at RT and then evaporated todryness under reduced pressure. The residue was triturated with water (1L) and the solid was collected by filtration, washing with more water(3×500 mL). The solid was dissolved in DCM (750 mL), dried (MgSO₄),filtered and evaporated under reduced pressure to give the titlecompound (107 g, 99%) as a pale yellow solid. ¹H NMR (400 MHz, CDCl₃)8.43 (1H, d), 7.90 (1H, dd), 7.75-7.72 (2H, m), 7.47-7.44 (2H, m), 4.21(2H, q), 4.11-4.05 (2H, m), 3.63-3.48 (3H, m), 1.97-1.79 (4H, m), 1.13(3H, dd).

Step 2: Ethyl2-(4-chlorobenzoyl)-3-fluoro-5-(4-fluorotetrahydro-2H-pyran-4-carbonyl)benzoate

A three neck flask was fitted with a nitrogen inlet, a thermometer, anda pressure equalising dropping funnel. The flask was charged with ethyl2-(4-chlorobenzoyl)-3-fluoro-5-(tetrahydro-2H-pyran-4-carbonyl)benzoate(54.0 g, 129 mmol) and dry THF (560 mL). The mixture was then cooled to−78° C. and LHMDS (170 mL. 170 mmol, 1M in THF) was added at a steadyrate such that the internal reaction temperature did not exceed −60° C.The mixture was stirred at −78° C. for 20 min, and then a solution ofN-fluorobenzenesulfonimide (53.14 g, 169 mmol) in THF (560 mL) was addedsteadily ensuring the internal temperature did not exceed −60° C. Themixture was stirred at −78° C. for 20 min, and was then allowed to warmto room temperature (˜1 h). The reaction was quenched with water (500mL) and then extracted with ethyl acetate (3×250 mL). The combinedorganic extracts were dried (MgSO₄), filtered, and evaporated underreduced pressure to give a crude residue which was purified by silicacolumn chromatography (340 g cartridge, gradient elution 0 to 40% EtOAcin iso-hexane) to give the title compound (46.2 g, 82%) as a colourlesssolid. MS: [M+H]⁺=437.

Step 3:2-(4-Chlorobenzoyl)-3-fluoro-5-(4-fluorotetrahydro-2H-pyran-4-carbonyl)benzoicacid

2-(4-chlorobenzoyl)-3-fluoro-5-(4-fluorotetrahydro-2H-pyran-4-carbonyl)benzoate(46.2 g, 105 mmol) in THF (260 mL) and methanol (260 mL) was added 2MNaOH solution (530 mL). The resulting orange solution was stirred atroom temperature for 1 h. Diethyl ether (500 mL) was added and thelayers were separated. The aqueous phase was adjusted to pH 1 usingconcentrated HCl, and the resulting mixture was extracted with ethylacetate (2×500 mL). The combined organic extracts were dried (MgSO₄),filtered and evaporated under reduced pressure to give the titlecompound (37.4 g, 87%) as a colourless solid. The product was deemedsufficiently pure to be used in the subsequent step. ¹H NMR (400 MHz,CDCl₃) 8.62 (1H, s), 8.08 (1H, dd), 7.71 (2H, d), 7.46-7.43 (2H, m),4.01-3.84 (4H, m), 2.41-2.22 (2H, m), 2.04-1.96 (2H, m).

Preparation 54:(R)-2-(4-chlorobenzoyl)-3-fluoro-5-(1-(4-fluorotetrahydro-2H-pyran-4-yl)-1-hydroxypropyl)benzoicacid

Starting from2-(4-chlorobenzoyl)-3-fluoro-5-(4-fluorotetrahydro-2H-pyran-4-carbonyl)benzoicacid (Preparation 53). The title compound was prepared using proceduressimilar to those described in Preparation 52. ¹H NMR (400 MHz, CDCl₃)7.97 (1H, s), 7.71 (2H, d), 7.57 (1H, d), 7.43 (2H, d), 3.86 (2H, ddd),3.71-3.59 (3H, m), 2.28-2.18 (1H, m), 2.03-1.60 (5H, m), 0.76 (3H, t).[α]_(D) ²⁰=+16.06 (c 1.04, MeOH).

Preparation 55:2-(4-Chlorobenzoyl)-5-(cyclobutanecarbonyl)-3-fluorobenzoic acid

Starting from cyclobutylaldehyde, the title compound was prepared usingprocedures similar to those described in Example 73, steps 1 and 2. MS:[M−H]⁻=359

Preparation 56:trans-4-((tert-Butyldiphenylsilyl)oxy)cyclohexanecarbaldehyde

Step 1: trans-4-Hydroxy-N-methoxy-N-methylcyclohexanecarboxamide

To a solution of 4-hydroxycyclohexanecarboxylic acid (25 g, 173 mmol),EDCl (32 g, 208 mmol) and N,O-dimethylhydroxylamine hydrochloride (19 g,191 mmol) in DCM (500 mL) under nitrogen at room temperature was addedDIPEA (91 mL, 520 mmol) and the mixture stirred for 20 h. The reactionwas quenched with 2N aqueous HCl (50 mL), partitioned with water (400mL), layers shaken and separated, the aqueous re-extracted with DCM(2×150 mL). The combined organic extracts were dried (MgSO₄), filtered,and concentrated under reduced pressure to yield the desired product (21g) as a thick pale yellow oil. ¹H NMR (400 MHz, CDCl₃) 3.70 (3H, s),3.68-3.59 (1H, m), 3.18 (3H, s), 2.70-2.55 (1H, m), 2.10-2.02 (2H, m),1.88-1.80 (2H, m), 1.63-1.53 (2H, m), 1.38-1.26 (2H, m), OH missing.

Step 2:trans-4-((tert-Butyldiphenylsilyl)oxy)-N-methoxy-N-methylcyclohexane-1-carboxamide

trans-4-Hydroxy-N-methoxy-N-methylcyclohexanecarboxamide (12.2 g, 65mmol), was dissolved in DMF (200 mL) and stirred at room temperatureunder a nitrogen atmosphere. tert-butyl(chloro)diphenylsilane (19.7 g,71 mmol) was added, followed by imidazole (4.88 g, 71 mmol). Thereaction was stirred for 18 h. The DMF was evaporated under reducedpressure, and the resulting residue was re-dissolved in EtOAc (250 mL).The organic layer was washed with 4% aqueous LiCl solution (2×150 mL),and then dried (MgSO4), filtered, and evaporated under reduced pressure.The crude residue was purified by silica column chromatography (gradientelution 0 to 60% EtOAc in iso-Hex), to give the pure product as acolourless oil which crystallises upon standing (19.0 g, 69% yield). MS:[M+H]⁺=426.

Step 3: trans-4-((tert-Butyldiphenylsilyl)oxy)cyclohexanecarbaldehyde

trans-4-((tert-Butyldiphenylsilyl)oxy)-N-methoxy-N-methylcyclohexanecarboxamide(0.5 g, 1.17 mmol) was dissolved in dry THF (7.5 mL) under a nitrogenatmosphere. The solution was cooled to −78° C., and then DIBAL (1M inhexane, 2.11 mL, 2.11 mmol) was added dropwise. The mixture was stirredat −78° C. for 1.5 h and then quenched with 10% aqueous Rochelle saltsolution (10 mL). The mixture was allowed to warm to room temperatureand was then diluted further with EtOAc (40 mL) and more Rochelle saltsolution (15 mL). The mixture was stirred for 20 mins before beingtransferred to a separating funnel. The organic phase was collected, andthe aqueous phase was extracted with EtOAc (2×30 mL). The combinedorganic extracts were dried (MgSO₄), filtered, and evaporated underreduced pressure to give a crude residue which was used in next stepwithout further purification. ¹H NMR (400 MHz, CDCl₃) 9.56 (1H, s),7.67-7.65 (4H, m), 7.43-7.34 (6H, m), 3.64-3.55 (1H, m), 2.20-2.13 (1H,m), 1.95-1.80 (4H, m), 1.48-1.37 (2H, m), 1.28-1.20 (2H, m), 1.05 (9H,s).

Preparation 57:(−)-5-(1-(1-(tert-butoxycarbonyl)-4-fluoropiperidin-4-yl)-1-hydroxypropyl)-2-(4-chlorobenzoyl)-3-fluorobenzoicacid (*Both Isomers Separated and Isolated)

Step 1:5-(1-(tert-Butoxycarbonyl)-4-fluoropiperidine-4-carbonyl)-2-(4-chlorobenzoyl)-3-fluorobenzoicacid

A mixture of5-(1-(tert-butoxycarbonyl)piperidine-4-carbonyl)-2-(4-chlorobenzoyl)-3-fluorobenzoicacid (Example 80 step 2, 50 g, 0.102 mol) and NaOH (4.32 g, 0.108 mol)was stirred in anhydrous THF (250 mL) and anhydrous MeOH (90 mL) untilall the NaOH dissolved. The solution was evaporated under reducedpressure and the residue dissolved in anhydrous THF (400 mL) and addedover 1 minute to a stirred solution of 1M LHMDS in hexanes (125 mL) inanhydrous THF (100 mL) at −40° C. under nitrogen. The mixture wasstirred for 20 minutes at −40° C. prior to the addition of a solution ofN-fluorobenzenesulfonimide (48.6 g, 0.154 mol) in anhydrous THF (400 mL)in a steady stream over 1 minute. On complete addition the mixture wasstirred with cooling in a bath at −40° C. for 20 minutes. The mixturewas quenched with water (500 mL), stirred at room temperature for 30minutes, the pH adjusted to pH2 with 2N HCl and then the aqueous wasextracted with EtOAc (2×750 mL). The combined organics were dried(MgSO₄) and the solvent evaporated. The residue was triturated with DCM(500 mL) and the solid filtered, washed with DCM and dried to afford thetitle compound as a colourless solid (31.3 g, 60%). MS [M−H]⁻=506.

Step 2:(−)-5-(1-(1-(tert-butoxycarbonyl)-4-fluoropiperidin-4-yl)-1-hydroxypropyl)-2-(4-chlorobenzoyl)-3-fluorobenzoicacid

To anhydrous THF (130 mL) at −50° C. under nitrogen was added a 1.72 Msolution of EtLi in dibutyl ether (38.4 mL, 65.96 mmol) followed by 1 Mdiethylzinc in hexanes (66.4 mL). This was stirred at −50° C. for 70minutes prior to addition of a solution of5-(1-(tert-butoxycarbonyl)-4-fluoropiperidine-4-carbonyl)-2-(4-chlorobenzoyl)-3-fluorobenzoicacid (13.4 g, 26.38 mmol) in anhydrous THF (130 mL) in a gentle streamover 1 minute. On complete addition the mixture was stirred at −50° C.for 20 minutes, quenched by careful addition of water (200 mL), warmedto room temperature, acidified with 1M HCl and extracted into EtOAc(2×500 mL). Combined extracts were dried (MgSO₄) and the solventevaporated under reduced pressure. The residue was triturated withisohexane (500 mL), the solvent decanted and the colourless solid driedto afford the title compound as the racemate. (13.9 g, 99%). MS[M−H]⁻=536. The racemate (11.2 g) was separated by SFC to afford thetitle compound as the slow running isomer (5.11 g, 45% yield).

(+)-5-(1-(1-(tert-butoxycarbonyl)-4-fluoropiperidin-4-yl)-1-hydroxypropyl)-2-(4-chlorobenzoyl)-3-fluorobenzoicacid: Fast running isomer* ¹H NMR (400 MHz, CDCl₃) 7.97 (1H, s), 7.72(2H, d), 7.54 (1H, d), 7.43 (2H, d), 4.01-4.01 (2H, m), 3.00-2.89 (2H,m), 2.28-2.19 (1H, m), 2.08-1.98 (2H, m), 1.81-1.50 (3H, m), 1.43 (9H,s), 0.75 (3H, dd), exchangeable protons not observed. [α]_(D) ²⁰=+31.41°(c 1, MeOH).

(−)-5-(1-(1-(tert-butoxycarbonyl)-4-fluoropiperidin-4-yl)-1-hydroxypropyl)-2-(4-chlorobenzoyl)-3-fluorobenzoicacid: Slow running isomer* ¹H NMR (400 MHz, CDCl₃) 7.97 (1H, s), 7.72(2H, d), 7.54 (1H, d), 7.43 (2H, d), 4.01-4.01 (2H, m), 3.00-2.89 (2H,m), 2.28-2.19 (1H, m), 2.08-1.98 (2H, m), 1.81-1.50 (3H, m), 1.43 (9H,s), 0.75 (3H, dd), exchangeable protons not observed. [α]_(D) ²⁰=−31.33°(c 1, MeOH).

Preparation 58: (2-Bromo-4-methylphenyl)methanamine

Prepared in a similar manner to that described in Example 33, Step 1;from 2-bromo-4-methylbenzonitrile. ¹H NMR (400 MHz, CDCl₃) 7.37 (1H, s),7.25 (1H, d), 7.08 (1H, d), 3.86 (2H, s), 2.31 (3H, s).

Preparation 59: (2-Bromo-4-methoxyphenyl)methanamine

Prepared in a similar manner to that described Example 33, Step 1; from2-bromo-4-methylbenzonitrile. ¹H NMR (400 MHz, CDCl₃) 7.26 (1H, d), 7.11(1H, d), 6.84 (1H, dd), 3.85 (2H, s), 3.79 (3H, s), 1.5 (2H, br s).

Preparation 60:(S)-5-(1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1-hydroxypropyl)-2-(4-chlorobenzoyl)-3-fluorobenzoicacid

Steps 1-2

Starting from the piperidine ketone (Examples 80 and 81, step 2, 11.0 g,23 mmol), Steps 1 and 2 were performed using a procedure similar to thatdescribed for Preparation 52, Step 1-2, The racemic mixture wasseparated by chiral SFC to give

(−)-tert-butyl-(S)-4-(1-(4-(4-chlorobenzoyl)-3-fluoro-5-(methoxycarbonyl)phenyl)-1-hydroxypropyl)piperidine-1-carboxylate(3 g). MS: [M+H]⁺=534, [α]_(D) ²⁰=−34.15 (c 1.18, MeOH).

and

(+)-tert-butyl-(S)-4-(1-(4-(4-chlorobenzoyl)-3-fluoro-5-(methoxycarbonyl)phenyl)-1-hydroxypropyl)piperidine-1-carboxylate(3.6 g). MS: [M+H]⁺=534, [α]_(D) ²⁰=+24.46 (c 1.02, MeOH).

Step 3:(S)-5-(1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1-hydroxypropyl)-2-(4-chlorobenzoyl)-3-fluorobenzoicacid

Using procedures similar to those described in Preparation 52 Step 3,(−)-tert-butyl(S)-4-(1-(4-(4-chlorobenzoyl)-3-fluoro-5-(methoxycarbonyl)phenyl)-1-hydroxypropyl)piperidine-1-carboxylate(3.0 g, 5.6 mmol) gave 3.1 g of the title compound. MS: [M+H]⁺=518,[α]_(D) ²⁰=−37.51 (0.97 q/100 mL),

Preparation 61:2-(4-Chlorobenzoyl)-3-fluoro-5-(pyridine-2-carbonyl)benzoic acid

The title compound was prepared using procedures similar to thosedescribed in Example 73 (step 1-2), but using pyridine-2-carboxaldehydein step 1. Iodine (2 mol. Eq.), K₂CO₃ (2 mol eq.), Ki (0.25 mol eq) inwater (90° C.) was used as alternative oxidation conditions in Step 2.MS: [M+H]⁺=384.

Preparation 62: Prop-2-en-1-yl(2S,3S)-3-amino-3-(4-chlorophenyl)-2-methylpropanoate

Step 1:N-[(1Z)-(4-Chlorophenyl)methylidene]-2-methylpropane-2-(R)sulfinamide

(R)-2-methylpropane-2-sulfinamide (18.1 g, 150 mmol),4-chlorobenzaldehyde (20.0 g, 143 mmol) and Cs₂CO₃ (51.0 g, 157 mmol)were suspended in DCM (150 mL) and stirred at room temperature for 16 h.The mixture was then filtered through Celite and the volatiles wereremoved in vacuo to give the desired product as a white solid (26.0 g,75% yield). LCMS: [M+H]⁺=244.

Step 2: (4-Methoxyphenyl)methyl(2S,3S)-3-(4-chlorophenyl)-2-methyl-3-[(2-methylpropane-2-(R)-sulfinyl)amino]propanoate

n-BuLi (2.5 M in hexane, 16.8 mL, 45 mml) was slowly added to a solutionof diisopropylamine (6.3 mL, 45 mmol) in THF (20 mL) at 0° C. and thereaction stirred for 30 min. at the same temperature. The mixture wasthen cooled to −78° C. and (4-methoxyphenyl)methyl propanoate (7.2 mL,40 mmol) was slowly added, keeping the temperature below −70° C. After30 min. chlorotriisopropoxytitanium(IV) (1M in hexane, 80 mL, 84 mmol)was added to the reaction mixture and stirring was maintained forfurther 30 min at −78° C. Finally, a solution ofN-[(1Z)-(4-chlorophenyl)methylidene]-2-methylpropane-2-(R)sulfinamide(5.0 g, 20 mmol) in THF (15 mL) was slowly added and the reaction wasstirred for further 2 h at −78° C. NH₄Cl (aq), water and EtOAc wereadded to the reaction, the mixture was wormed up to room temperature andvigorously stirred for 30 min. to dissolve most of the solid. Theorganic phase was separated and the aqueous phase was extracted withEtOAc (3×). The organic phases were collected, dried over Na₂SO₄ andconcentrated in vacuo. The residue was columned on silica gel (gradient0-100% EtOAc in Petrol) to give the desired product as a yellow oil (5.1g, 58% yield). 1H NMR (400 MHz, DMSO-d6): 7.39-7.27 (2H, m), 7.24 (2H,d), 7.00 (2H, t), 6.91-6.80 (2H, m), 5.72-5.63 (1H, m), 4.88-4.73 (2H,m), 4.24 (1H, t), 3.75 (3H, s), 2.99-2.87 (1H, m), 1.28 (3H, d),1.02-0.90 (9H, m).

Step 3:(2S,3S)-3-(4-Chlorophenyl)-2-methyl-3-[(2-methylpropane-2-(R)-sulfinyl)amino]propanoicacid

TFA (12 mL) was added to a solution of (4-methoxyphenyl)methyl(2S,3S)-3-(4-chlorophenyl)-2-methyl-3-[(2-methylpropane-2-(R)-sulfinyl)amino]propanoate(6.0 g, 13.7 mmol) in DCM (20 mL) and the reaction was stirred at roomtemperature for 1 h. The volatiles were removed in vacuo and the residuewas partitioned between 1M HCl and EtOAc. The aqueous phase wasextracted with EtOAc (3×), the organic phases were collected, dried overNa₂SO₄ and concentrated in vacuo to give the give the desired product ada light brown solid which was used without further purifications in thenext step. LCMS: [M+H]⁺=318.

Step 4: Prop-2-en-1-yl(2S,3S)-3-(4-chlorophenyl)-2-methyl-3-[(2-methylpropane-2-(R)-sulfinyl)amino]propanoate

Allyl bromide (2.3 mL, 26 mmol) was added to a suspension of(2S,3S)-3-(4-chlorophenyl)-2-methyl-3-[(2-methylpropane-2-(R)-sulfinyl)amino]propanoicacid (crude from previous step, ca. 13 mmol) and K₂CO₃ (5.4 g, 39 mmol)in DMF. The reaction mixture was stirred at room temperature for 2 h,quenched with water and extracted with EtOAc. The organic was dried overNa₂SO₄ and concentrated in vacuo. The residue was columned on silica gel(gradient 0-100% EtOAc in Petrol) to give the desired product as ayellow oil (2.8 g, 57% yield over 2 steps). 1H NMR (400 MHz, DMSO-d6):7.40-7.32 (2H, m), 7.29 (2H, d), 5.74-5.58 (2H, m), 5.15-5.02 (2H, m),4.41-4.31 (2H, m), 4.27 (1H, t), 3.00-2.88 (1H, m), 1.28 (3H, d), 1.01(9H, s).

Step 5: Prop-2-en-1-yl(2S,3S)-3-amino-3-(4-chlorophenyl)-2-methylpropanoate

HCl (4M in dioxane, 15 mL) was added to a solution of prop-2-en-1-yl(2S,3S)-3-(4-chlorophenyl)-2-methyl-3-[(2-methylpropane-2-(R)-sulfinyl)amino]propanoate(2.8 g, 7.8 mmol) in EtOH (20 mL) and the suspension was stirred at roomtemperature for 30 min. The volatiles were removed in vacuo and theresidue was partitioned between NaHCO₃ and EtOAc. The organic wascollected, dried over Na₂SO₄ and concentrated in vacuo to give thedesired product as a yellow oil (1.7 g, 86% yield). 1H NMR (400 MHz,DMSO-d6): 7.34 (4H, s), 5.81-5.68 (1H, m), 5.22-5.06 (2H, m), 4.46-4.33(2H, m), 4.07-3.94 (1H, m), 2.76-2.60 (1H, m), 1.96 (2H, s), 1.09 (3H,d).

Preparation 63: Ethyl 2-[2-(aminomethyl)-5-chlorophenoxy]acetatehydrochloride

Step 1: tert-Butyl N-[(4-chloro-2-hydroxyphenyl)methyl]carbamate

To a stirred solution of 4-chloro-2-hydroxybenzonitrile (1.57 g, 10.0mmol) in dry methanol (70 mL), cooled to 0° C., were added Boc₂O (4.36g, 20.0 mmol) and NiCl₂.6H₂O (0.24 g, 1.0 mmol). NaBH₄ (2.65 g, 70.0mmol) was then added in small portions over 30 min. The reaction wasexothermic and effervescent. The resulting reaction mixture containing afinely divided black precipitate was allowed to warm to room temperatureand left to stir for a further 1 h, at which point diethylenetriamine(1.1 mL, 20.0 mmol) was added. The mixture was allowed to stir for 30min before solvent evaporation. The residue was dissolved in DCM (50mL), piperidine (2 mL) was added and stirred for 30 min, then theorganic phase was washed with water and saturated NaHCO₃. The organiclayer was dried (MgSO₄) and the solvent removed in vacuo and the crudeproduct was purified by column chromatography to afford the titlecompound (1.47 g, 57%). MS:[M+H]⁺=256.

Step 2: Ethyl2-[2-({[(tert-butoxy)carbonyl]amino}methyl)-5-chlorophenoxy]acetate

To a solution of tert-butylN-[(4-chloro-2-hydroxyphenyl)methyl]carbamate (1.47 g, 5.7 mmol) in DMF(30 mL) was added K₂CO₃ (0.95 g, 6.9 mmol) and the mixture was stirredfor 30 min. Ethyl bromoacetate (1.4 mL, 8.55 mmol) was added and thestirring was continued for 2 hr. Water was added, the reaction mixturewas extracted with EtOAc, the organic phase was washed with brine (3×),dried and the solvent was evaporated. The crude material was purified bycolumn chromatography, eluted with petroleum ether-EtOAc 0-40% to affordthe title compound (1.64 g, 84%). MS:[M+H]⁺=243 (M-Boc).

Step 3: Ethyl 2-[2-(aminomethyl)-5-chlorophenoxy]acetate hydrochloride

To a solution of ethyl2-[2-({[(tert-butoxy)carbonyl]amino}methyl)-5-chlorophenoxy]acetate (1.8g, 5.25 mmol) in dioxane (20 mL) was added 4M dioxane —HCl and themixture was stirred for 16 hr. The solvent was evaporated to affordwhite solid (1.3 g, 89%). MS:[M+H]⁺=244.

Preparation 64:2-(4-chlorobenzoyl)-3-fluoro-5-(1-hydroxy-1-trans-4-hydroxycyclohexyl)propyl)benzoicacid (*Both Isomers Separated and Isolated)

Step 1:5-(trans-4-((tert-Butyldiphenylsilyl)oxy)cyclohexane-1-carbonyl)-2-(4-chlorobenzoyl)-3-fluorobenzoicacid

Starting fromtrans-4-((tert-butyldiphenylsilyl)oxy)cyclohexanecarbaldehyde(Preparation 56), the title compound was prepared using proceduressimilar to those described in Example 73, steps 1 and 2. MS: [M−H]⁻=641.

Step 2:5-(1-(trans-4-((tert-butyldiphenylsilyl)oxy)cyclohexyl)-1-hydroxypropyl)-2-(4-chlorobenzoyl)-3-fluorobenzoicacid

The title compound was prepared using the procedure described inPreparation 52, step 1, and the enantiomers were separated by chiralSFC.

(+)-5-(1-(trans-4-((tert-butyldiphenylsilyl)oxy)cyclohexyl)-1-hydroxypropyl)-2-(4-chlorobenzoyl)-3-fluorobenzoicacid: *fast running isomer ¹H NMR (400 MHz, CDCl₃) 7.8 (1H, s),7.70-7.63 (6H, m), 7.43-7.34 (9H, m), 3.55-3.46 (1H, m), 1.94-1.78 (5H,m), 1.43-1.24 (3H, m), 1.03 (9H, s), 0.96-0.83 (3H, m), 0.69 (3H, t),Exchangeable not observed. MS: [M−H]−=671. [α]_(D) ²⁰=+27.65 (c 1.0MeOH).

(−)-5-(1-(trans-4-((tert-butyldiphenylsilyl)oxy)cyclohexyl)-1-hydroxypropyl)-2-(4-chlorobenzoyl)-3-fluorobenzoicacid: *slow running isomer ¹H NMR (400 MHz, CDCl₃) 7.79 (1H, s),7.70-7.63 (6H, m), 7.44-7.33 (9H, m), 3.54-3.48 (1H, m), 1.96-1.75 (5H,m), 1.46-1.16 (3H, m), 1.03 (9H, s), 0.96-0.85 (3H, m), 0.69 (3H, t),Exchangeable not observed. MS: [M−H]−=671. [α]_(D) ²⁰=−24.62 (c 1.0,MeOH).

Step 3:2-(4-chlorobenzoyl)-3-fluoro-5-(1-hydroxy-1-trans-4-hydroxycyclohexyl)propyl)benzoicacid

(−)-5-1-(trans-4-((tert-Butyldiphenylsilyl)oxy)cyclohexyl)-1-hydroxypropyl)-2-(4-chlorobenzoyl)-3-fluorobenzoicacid (3.5 g, 5.2 mmol) was dissolved in THF (70 mL) and the mixture wastreated with TBAF (1M in THF, 20.7 mL, 20.7 mmol) and heated overnightat 60° C. The reaction was quenched with saturated aqueous NaHCO₃solution and extracted with ethyl acetate (2×75 mL). The combinedorganic layers were dried (MgSO₄), filtered and evaporated to drynessunder reduced pressure to give a crude product. The residue was purifiedby column chromatography (gradient elution, 20 to 100% ethyl acetate iniso-hexane (with 0.1% formic acid)) to give the title compound (1.92 g,85%) as a colourless oil. MS: [M−H]⁻=433.

Preparation 65:2-(4-chlorobenzoyl)-3-fluoro-5-(1-methyl-1H-pyrazole-3-carbonyl)benzoicacid

The title compound was prepared using procedures similar to thosedescribed in Example 72, Step 1 and Step 2, but using1-methyl-1H-pyrazole-3-carbaldehyde instead of1-methyl-1H-pyrazole-4-carboxaldehyde in Step 1; and manganese dioxidein 1,4-dioxane at 100° C. instead of TEMPO/sodium hypochlorite in Step2. MS [M+H]⁺=387

Example 1:(3R)-3-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-3-{[1-(hydroxymethyl)cyclopropyl]methoxy}-6-(2-hydroxypropan-2-yl)-2,3-dihydro-1H-isoindol-1-one

To a solution of MeMgBr (3M THF, 0.97 mL, 2.91 mmol) in THF (4.0 mL) atroom temperature was added Zn(II)Cl₂ (30 mgs, 0.22 mmol) and theresulting solution stirred at this temperature for 1 hour. The solutionwas cooled to 0° C. before the addition of a cool solution of6-acetyl-2-(4-chlorobenzyl)-3-(4-chlorophenyl)-3-((3′-(hydroxymethyl)cyclopropyl)methoxy)isoindolin-1-one (Preparation 15) (573 mgs, 1.12mmol) in THF (4.0 mL) and the resulting mixture stirred at 0° C. for 2hours. The reaction was quenched by the addition of a saturated solutionof NH₄Cl and the resulting mixture extracted with EtOAc (×3). Thecombined organic phases were washed with brine, dried (MgSO₄), filteredand concentrated in vacuo. Purification on silica gel (Biotage SP4)eluting with 20%-80% EtOAc/Pet gave product as a clear gum (320 mg;54%). Separation by chiral HPLC (Chrialpak IA 250×10 mm i.d., 75%heptane, 2-propanol, 4.5 mL/min) gave the title compound (Example 1)(R)-2-(4-Chlorobenzyl)-3-(4-chlorophenyl)-3-((3′-(hydroxymethyl)cyclopropyl)methoxy)-6-(2-hydroxypropan-2-yl)isoindolin-1-one. δ_(H) (500 MHz,CD₃OD) 0.12-0.23 (2H, m, 3′-CH₂), 0.37-0.45 (2H, m, 3′-CH₂′), 1.56 (6H,s, (CH₃)₂), 2.76 (1H, d, J=9.0, 2′-H), 2.88 (1H, d, J=9.0, 2′-H′), 3.42(1H, d, J=11.2, 4′-H), 3.58 (1H, d, J=11.2, 4′-H′), 4.40 (1H, d, J=15.1,N—CH), 4.45 (1H, d, J=15.1, N—CH′), 7.07-7.14 (4H, m, Ar—H), 7.15-7.22(5H, m, Ar—H & 4-H), 7.76 (1H, dd, J=1.2, 8.1, 5-H), 8.02 (1H, d, J=1.2,7-H); HRMS, Found; M⁺ 526.1540/.

Example 2:(3R)-3-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-4-fluoro-3-{[1-(hydroxymethyl)cyclopropyl]methoxy}-6-(2-hydroxypropan-2-yl)-2,3-dihydro-1H-isoindol-1-one

In a microwave vial was added Hg(OAc)₂ (145 mg, 0.456 mmol) and water(0.3 mL). After stirring for 15 min, THF (0.25 mL) was added, followedby a solution of2-(4-chlorobenzyl)-3-(4-chlorophenyl)-4-fluoro-3-((1-(hydroxymethyl)cyclopropyl)methoxy)-6-(prop-1-en-2-yl)isoindolin-1-one(Preparation 14) (150 mg, 0.285 mmol) in THF (0.5 mL). The orangesolution was stirred at room temperature for 1.5 h, after which timeperchloric acid (60%, 7.5 μL) was added, with the orange colour fadingto yellow after 2.5 h. 1M aq. NaOH (0.8 mL) was added and the solutionturned brown, then NaBH₄ (22 mg, 0.570 mmol) was introduced and thecolour changed to metallic grey. The reaction mixture was left to stirfor 16 h, then filtered through Celite®, followed by a thiol cartridgeand the solvent removed in vacuo. FCC [petrol-ethyl acetate(100:0)→(80:20)→(50:50)→(20:80)] of the crude residue, followed bypreparative HPLC, afforded 28 mg, 20%, of a white solid. Separation ofthe two enantiomers was carried out by preparative chiral HPLC to give(R)-2-(4-Chlorobenzyl)-3-(4-chlorophenyl)-4-fluoro-3-((1-(hydroxymethyl)cyclopropyl)methoxy)-6-(2-hydroxypropan-2-yl)isoindolin-1-one(Example 2). ¹H NMR (500 MHz, CDCl₃): 7.77 (1H, d, 7-H), 7.37 (1H, dd,ArH), 7.20-7.26 (4H, m, 4×ArH), 7.10-7.16 (4H, m, 4×ArH), 4.55 (1H, d,NC—H′), 4.11 (1H, d, NC—H), 3.53 (1H, d, 4′-H′), 3.34 (1H, d, 4′-H),2.96 (1H, d, 2′-H′), 2.69 (1H, d, 2′-H), 1.55-1.64 (6H, 2×s, 2×CH₃),0.37-0.44 (2H, m, Cy-Py-H₂) and 0.08-0.23 (2H, m, Cy-Py-H). MS:[M-C₅H₉O₂]⁺ 442

Example 3:(3R)-3-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-3-(2-hydroxyethoxy)-6-(2-hydroxypropan-2-yl)-2,3-dihydro-1H-isoindol-1-one

The title compound was prepared from (Preparation 21) (0.062 g, 0.128mmol), ZnCl₂ (0.005 g, 0.035 mmol) and of MeMgCl (3M in THF) (0.15 mL,0.46 mmol) using a procedure similar to that described for Example 1.The product was obtained as a white foamy solid (0.030 g, 0.062 mmol,47%). Separation by preparative chiral prep HPLC gave Example 3. ¹H NMR(500 MHz, CDCl₃) δ (ppm) 1.50 (s, 1H), 1.62 (s, 6H), 1.82 (s, 1H),2.77-2.83 (m, 1H), 2.87-2.95 (m, 1H), 3.33-3.47 (m, 2H), 4.08 (d, 1H),4.64 (d, 1H), 7.09 (dd, 1H), 7.13-7.20 (m, 4H), 7.20-7.25 (m, 4H), 7.71(dd, 1H), 8.0 (d, 1H); MS(ES+) m/z 486.3 [M+H]⁺;

Example 4:(3R)-3-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-3-{[3-(hydroxymethyl)oxetan-3-yl]methoxy}-6-(2-hydroxypropan-2-yl)-2,3-dihydro-1H-isoindol-1-one

Starting from Preparation 23. The title compound was prepared in asimilar fashion to Example 1, but using 4.5 mol eq. of MeMgCl. ¹H NMR(500 MHz, CDCl₃) δ (ppm) 1.60 (s, 1H, OH), 1.62 (s, 3H, C(CH₃)₂), 1.63(s, 3H, C(CH₃)₂), 1.92 (s, 1H, OH), 2.99 (d, 1H, J=9.2 Hz, OCHHC), 3.03(d, 1H, J=9.2 Hz, OCHHC), 3.67-3.75 (m, 2H, CCH₂OH), 4.18 (d, 1H, J=15.2Hz, NCHH), 4.25 (d, 1H, J=6.3 Hz, oxetane CHH), 4.30 (d, 1H, J=6.2 Hz,oxetane CHH), 4.33 (d, 1H, J=6.3 Hz, oxetane CHH), 4.36 (d, 1H, J=6.2Hz, oxetane CHH), 4.56 (d, 1H, J=15.2 Hz, NCHH), 7.07 (d, 1H, J=7.9 Hz,isoindolinone-H), 7.09-7.19 (m, 6H, Ar—H), 7.22 (d, 2H, J=8.9 Hz, Ar—H),7.73 (dd, 1H, J=8.0, 1.7 Hz, isoindolinone-H), 8.03 (d, 1H, J=1.7 Hz,isoindolinone-H); MS(ES+) m/z 586.3 [M+HCOO⁻]⁻;

Example 5:1-({[(1R)-1-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-5-(2-hydroxypropan-2-yl)-3-oxo-2,3-dihydro-1H-isoindol-1-yl]oxy}methyl)cyclopropane-1-carboxylicacid

To a solution of2-(4-chlorobenzyl)-3-(4-chlorophenyl)-3-((1-(hydroxymethyl)cyclopropyl)methoxy)-6-(2-hydroxypropan-2-yl)isoindolin-1-one(Example 1) (110 mg, 0.21 mmol), RuCl₃.H₂O (10 mg, 0.02 mmol) in amixture of EtOAc (0.7 mmol/mL alcohol), MeCN (0.7 mmol/mL alcohol), andwater (0.4 mmol/mL alcohol), was added sodium periodate (4.1 mol eq.)and stirred at rt for 15 min before being diluted with EtOAc (0.04mmol/mL alcohol) and filtered through a Celite plug. The filtrates werewashed with water (0.04 mmol/mL alcohol) and the aqueous was extractedwith EtOAc (2×0.04 mmol/mL alcohol). The combined organic phases werewashed with brine (0.02 mmol/mL alcohol), dried (MgSO₄) and concentratedin vacuo., sodium periodate (185 mg, 0.86 mmol), MeCN (0.6 mL), EtOAc(0.6 mL) and water (1.0 mL). Purification (SP4, silica, EtOAc/petrol(0.1% AcOH), 60%) followed by semi-preparative chiral HPLC (C-18 silica,MeCN/0.1% aq. formic acid, 40%) gave Example 5 as a white solid (54 mg,48%). ¹H NMR (500 MHz, CDCl₃) δ 0.48-0.52 (1H, m, H-cyclopropane),0.57-0.61 (1H, m, H-cyclopropane), 1.18-1.21 (1H, m, H-cyclopropane),1.25-1.29 (1H, m, H-cyclopropane), 1.60 (3H, s, CH₃), 1.62 (3H, s, CH₃),2.71 (1H, d, J=9.6 Hz, -iso-OCHH), 3.16 (1H, d, J=9.6 Hz, -iso-OCHH),4.19 (1H, d, J=15.1 Hz, NCHH), 4.58 (1H, d, J=15.1 Hz, NCHH), 7.09-7.19(9H, m, H—Ar), 7.71 (1H, dd, J=1.8, 8.0 Hz, H-5), 7.98 (1H, d, J=1.8 Hz,H-7); LRMS (ES⁻) m/z 538.3 [M−H]⁻;

Example 6:(3R)-3-(4-chlorophenyl)-2-[(1S)-1-(4-chlorophenyl)ethyl]-3-(2,3-dihydroxy-2-methylpropoxy)-6-(2-hydroxypropan-2-yl)-2,3-dihydro-1H-isoindol-1-one

(*As a Mixture of Isomers at the Position Shown)

(S)-3-(4-Chlorophenyl)-2-((S)-1-(4-chlorophenyl)ethyl)-3-((2-(hydroxymethyl)allyl)oxy)-6-(prop-1-en-2-yl)isoindolin-1-one,Preparation 24, (90 mg, 0.18 mmol), Hg(OAc)₂ (140 mg, 0.44 mmol), water(0.5 mL), THF (0.5 mL), 6 M NaOH (0.2 mL) and NaBH₄ (269 mg, 7.1 mmol).Purification (SP4, silica, EtOAc/petrol, 80%) gave Example 6 as amixture of 2 isomers (27 mg, 28%). ¹H NMR (500 MHz, CDCl₃) δ mixture ofdiastereoisomers 0.95 (3H, s, -iso-OCH₂C(OHCH₃)CH₂OH), 1.00 (3H, s,-iso-OCH₂C(OHCH₃)CH₂OH), 1.64 (6H, s, C(CH₃)₂OH), 1.65 (6H, s,C(CH₃)₂OH), 1.67 (3H, d, J=7.3 Hz, NCHCH₃), 1.71 (3H, d, J=7.5 Hz,NCHCH₃), 1.87 (2H, br s, OH×2), 2.00 (2H, br s, OH×2), 2.65-2.73 (4H, m,-iso-OCH₂×2), 3.23-3.36 (4H, m, CH₂OH×2), 4.24 (1H, q, J=7.5 Hz,NCHCH₃), 4.28 (1H, q, J=7.3 Hz, NCHCH₃), 7.01 (1H, d, J=7.9 Hz, H-4),7.02 (1H, d, J=7.9 Hz, H-4), 7.28-7.36 (6H, m, H—Ar), 7.55-7.57 (2H, m,H—Ar), 7.71-7.74 (2H, m, H-5), 7.98-7.99 (2H, m, H-7). LRMS (ES⁺) m/z566.4 [M+Na]⁺.

Example 7:(3R)-3-(4-chlorophenyl)-2-[(1S)-1-(4-chlorophenyl)ethyl]-3-{[1-(hydroxymethyl)cyclopropyl]methoxy}-6-(2-hydroxypropan-2-yl)-2,3-dihydro-1H-isoindol-1-one

Example 7 was prepared from Preparation 28 using similar procedure tothose described in Example 1. NMR (500 MHz, CDCl₃) δ 0.33-0.36 (1H, m),0.42-0.45 (1H, m), 0.47-0.54 (2H, m), 1.53 (3H, s), 1.55 (3H, s), 1.84(3H, d), 2.89 (1H, d), 3.21 (1H, d), 3.56 (2H), 4.28 (1H, q)), 6.92-6.98(9H, m), 7.63 (1H, dd), 7.85 (1H, d); MS (ES+) 540.5 [M+H]⁺

Examples 8 and 9:(3R)-3-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-6-(1,2-dihydroxypropan-2-yl)-3-{[1-(hydroxymethyl)cyclopropyl]methoxy}-2,3-dihydro-1H-isoindol-1-one

*The Two Separate Epimers at the Position Shown

To a solution of2-(4-chlorobenzyl)-3-(4-chlorophenyl)-3-((1-(hydroxymethyl)cyclopropyl)methoxy)-6-(prop-1-en-2-yl)isoindolin-1-one,Preparation 13 (1.20 g, 2.36 mmol) in acetone/water (18 mL/7.1 mL) wasadded methyl morpholine-N-oxide (318 mg, 2.71 mmol) and OsO₄ (2.5 wt %in tBuOH, 0.90 mL, 0.09 mmol) and the resulting yellow/orange solutionstirred at RT for 3.5 h. The reaction was diluted with DCM (125 mL),washed with saturated aqueous sodium sulphite (125 mL), dried over MgSO₄and concentrated under vacuum. MPLC (1:1 petrol/EtOAc to 100% EtOAc)gave the product as a white solid as a mixture of 4 diastereoisomers(592 mg, 46%). Purification by preparative chiral HPLC (324 mg,Chiralpak IA 250×10 mm, 92.5:7.5 Heptane/Ethanol) gave—

Example 8 (isomer 1): δ_(H) (500 MHz, CDCl₃) 0.13-0.16 (2H, m, 2×c-PrH),0.40-0.42 (2H, m, 2×c-PrH), 1.57 (3H, s, CH₃), 2.64 (1H, d, J=9.4 Hz,CHH′), 2.84 (1H, d, J=9.4 Hz, CHH′), 3.35 (1H, d, J=11.3 Hz, CHH′), 3.49(1H, d, J=11.3 Hz, CHH′), 3.69 (1H, d, J=11.0 Hz, CHH′), 3.79 (1H, d,J=11.0 Hz, CHH′), 4.19 (1H, d, J=14.9 Hz, CHH′), 4.54 (1H, d, J=14.9 Hz,CHH′), 7.12-7.21 (9H, m, 9×ArH), 7.70 (1H, dd, J=1.7 and 7.9 Hz, ArH),7.97 (1H, d, J=1.7 Hz, ArH).

Example 9 (isomer 2): δ_(H) (500 MHz, CDCl3) 0.14-0.15 (2H, m, 2×c-PrH),0.40-0.41 (2H, m, 2×c-PrH), 1.57 (3H, s, CH₃), 2.63 (1H, d, J=9.4 Hz,CHH′), 2.85 (1H, d, J=9.4 Hz, CHH′), 3.34 (1H, d, J=11.3 Hz, CHH′), 3.49(1H, d, J=11.3 Hz, CHH′), 3.69 (1H, d, J=11.0 Hz, CHH′), 3.81 (1H, d,J=11.0 Hz, CHH′), 4.19 (1H, d, J=14.9 Hz, CHH′), 4.54 (1H, d, J=14.9 Hz,CHH′), 7.13-7.21 (9H, m, 9×ArH), 7.69 (1H, d, J=7.8 Hz, ArH), 7.98 (1H,s, ArH).

Examples 10 and 11:(3R)-3-(4-chlorophenyl)-2-[(1S)-1-(4-chlorophenyl)ethyl]-6-(2-hydroxy-1-methoxypropan-2-yl)-3-{[1-(hydroxymethyl)cyclopropyl]methoxy}-2,3-dihydro-1H-isoindol-1-one

*The Two Separate Epimers at the Position Shown

At 0° C., to a solution of(3R)-3-((1-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)methoxy)-3-(4-chlorophenyl)-2-((S)-1-(4-chlorophenyl)ethyl)-6-(2-hydroxy-1-methoxypropan-2-yl)isoindolin-1-one, Preparation 31 (80 mg, 0.12 mmol), in THF(4 mL) was added TBAF (1.0 M in THF, 0.13 mL, 0.13 mmol) and thereaction stirred at 0° C. for 1 h then at RT for 18 h. The reaction wasdiluted with water (20 mL), neutralised with 1.0 M aqueous HCl,extracted into EtOAc (2×25 mL), washed with brine (50 mL) and dried overMgSO₄. MPLC (1:1 petrol/EtOAc to 100% EtOAc) and semi-preparative HPLC(ACE 5 C18-AR 150×4.6 mm i.d., 5 um, 55:45 Acetonitrile/Water+0.1% v/vFormic Acid) gave product as a white solid as a diastereoisomericmixture (36 mg, 53%); MS (ES+) 570.4 [M+H]⁺; Purification by preparativechiral HPLC (82 mg, Chiralpak IC 250×10 mm Mobile Phase: Heptane/Ethanol87.5:12.5) gave:—

Example 11 (*isomer 1): δ_(H) (500 MHz, CDCl3) 0.32-0.36 (1H, m, c-PrH),0.42-0.46 (1H, m, c-PrH), 0.47-0.53 (2H, m, 2×c-PrH), 1.44 (3H, s, CH₃),1.83 (3H, d, J=7.3 Hz, CHCH3), 2.89 (1H, d, J=9.5 Hz, CHH′), 3.21 (1H,d, J=9.5 Hz, CHH′), 3.32 (3H, s, OCH3), 3.43 (1H, d, J=9.2 Hz, CHH′),3.54 (1H, d, J=9.2 Hz, CHH′), 3.56 (2H, s, CH₂), 4.28 (1H, q, J=7.3 Hz,CHCH3), 6.92-6.99 (9H, m, 9×ArH), 7.62 (1H, dd, J=1.7 and 8.0 Hz, ArH),7.81 (1H, d, J=1.7 Hz, ArH). m/z 468.4 [M-OCH2C(CH₂—CH₂)CH₂OH]⁺

Example 10 (*isomer 2): 1H-NMR δ_(H) (500 MHz, CDCl₃) 0.32-0.36 (1H, m,c-PrH), 0.42-0.46 (1H, m, c-PrH), 0.47-0.53 (2H, m, 2×c-PrH), 1.46 (3H,s, CH₃), 1.83 (3H, d, J=7.3 Hz, CHCH₃), 2.87 (1H, d, J=9.5 Hz, CHH′),3.22 (1H, d, J=9.5 Hz, CHH′), 3.32 (3H, s, OCH₃), 3.41 (1H, d, J=9.2 Hz,CHH′), 3.51 (1H, d, J=9.2 Hz, CHH′), 3.56 (2H, s, CH₂), 4.28 (1H, q,J=7.3 Hz, CHCH₃), 6.92-6.99 (9H, m, 9×ArH), 7.64 (1H, dd, J=1.7 and 7.9Hz, ArH), 7.79 (1H, d, J=1.7 Hz, ArH).: m/z 468.4[M-OCH2C(CH₂—CH₂)CH₂OH]⁺

Examples 12 and 13:(3R)-3-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-6-[1-(dimethylamino)-2-hydroxypropan-2-yl]-3-{[1-(hydroxymethyl)cyclopropyl]methoxy}-2,3-dihydro-1H-isoindol-1-one

(*Two Isomers at the Position Shown)

Deprotection of Preparation 34 using a similar procedure to thatdescribed for Example 10 followed by purification by preparative chiralHPLC gave the two diastereoisomers:

Example 12 (*isomer 1): 1H NMR (500 MHz, CDCl₃) 0.12-0.20 (2H, m),0.36-0.45 (2H, m), 1.83 (3H, s), 2.58 (1H, d), 2.68-2.29 (3H, m), 2.89(1H, d), 2.99-3.00 (3H, m), 3.29 (1H, d), 3.39-3.42 (1H, m), 3.55 (1H,d), 3.62-3.66 (1H, m), 4.18 (1H, d), 4.54 (1H, d), 7.11-7.22 (9H, m),7.86 (1H, d), 7.94 (1H, s). MS:[M+H]⁺=569.5.

Example 13 (* isomer 2): 1H NMR (500 MHz, CDCl3) 0.12-0.23 (2H, m),0.36-0.42 (2H, m), 1.80 (3H, s), 2.42 (1H, d), 2.64 (3H, s), 2.92 (1H,d), 2.99-3.00 (3H, m), 3.15 (1H, d), 3.40-3.45 (1H, m), 3.58-3.63 (2H,m), 4.17 (1H, d), 4.53 (1H, d), 7.11-7.15 (4H, m), 7.19-7.23 (5H, m),7.85 (1H, s), 7.96 (1H, d). MS:[M+H]⁺=569.5.

Example 14:(3S)-3-(4-chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-1-{[1-(hydroxymethyl)cyclopropyl]methoxy}-5-(2-hydroxypropan-2-yl)-3-oxo-2,3-dihydro-1H-isoindol-2-yl]propanoicacid

Starting from Preparation 40, Example 14 was prepared using similarprocedures to those described for Example 1. ¹H NMR (500 MHz, MeOD) δ0.40-0.44 (4H, m, 4×c-PrH), 1.47 (6H, s, 2×CH₃), 2.91 (1H, d, J=9.2 Hz,CHH′), 3.09-3.21 (2H, m, CHH′ and CHCHH′), 3.51 (2H, s, CH₂), 3.73 (1H,dd, J=11.1 and 16.2 Hz, CHCHH′), 4.64 (1H, dd, J=3.6 and 11.1 Hz,CHCHH′), 6.89-6.97 (8H, m, 8×ArH), 7.02 (1H, d, J=8.0 Hz, ArH), 7.65(1H, dd, J=1.7 and 8.0 Hz, ArH), 7.89 (1H, d). MS. 582.1 (M−H⁺)⁻

Example 15:(3R)-3-(4-chlorophenyl)-2-[(1S)-1-(4-chlorophenyl)ethyl]-6-(1,2-dihydroxypropan-2-yl)-3-{[1-(hydroxymethyl)cyclopropyl]methoxy}-2,3-dihydro-1H-isoindol-1-one

Starting from(R)-3-(4-chlorophenyl)-2-((S)-1-(4-chlorophenyl)ethyl)-3-((1-(hydroxymethyl)cyclopropyl)methoxy)-6-(prop-1-en-2-yl)isoindolin-1-one(Preparation 27); Example 15 was prepared by using procedures similar tothose described for Example 8. Product was obtained as a white solid asa diastereoisomeric mixture (65 mg, 31 (500 MHz, CDCl₃) δ 0.34-0.36 (1H,m, c-PrH), 0.43-0.52 (3H, m, 3×c-PrH), 1.49-1.50 (3H, m, CH₃), 1.82-1.84(3H, m, NCHCH₃), 2.89-2.92 (1H, m, alkyl-CH), 3.18-3.21 (1H, m,alkyl-CH), 3.51-3.56 (2H, m, 2×alkyl-CH), 3.58-3.63 (1H, m, alkyl-CH),3.71-3.75 (1H, m, alkyl-CH), 4.28 (1H, q, J=7.3 Hz, NCHCH₃), 6.92-6.97(8H, m, 8×ArH), 7.00 (1H, d, J=7.9 Hz, ArH), 7.60-7.62 (1H, m, ArH),7.84-7.85 (1H, m, ArH); MS (ES+) 454.3 [M−HOCH₂(c-Pr)CH₂O]⁻;

Example 16:(3R)-3-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-3-(3-hydroxy-3-methylbutoxy)-6-(2-hydroxypropan-2-yl)-2,3-dihydro-1H-isoindol-1-one

Starting from Preparation 41, Example 16 was prepared using similarprocedure to those described in Example 1. Purification by chrial HPLC(Chiralpak IC 250×10 mm, Mobile Phase: Heptane/Ethanol 80:20): gaveExample 16:(R)-2-(4-Chlorobenzyl)-3-(4-chlorophenyl)-3-(3-hydroxy-3-methylbutoxy)-6-(2-hydroxypropan-2-yl)isoindolin-1-one(39 mg). ¹H NMR (500 MHz, CDCl₃) δ 0.98 (3H, s, CH₃), 1.02 (3H, s, CH₃),1.13-1.19 (1H, m, CH), 1.35-1.41 (1H, m, CH), 1.55 (3H, s, CH₃), 1.56(3H, s, CH₃), 2.75-2.80 (1H, m, CH), 2.86-2.91 (1H, m, CH), 3.91 (1H, d,J=14.9 Hz, NCHH′), 4.65 (1H, d, J=14.9 Hz, NCHH′), 7.03 (1H, d, J=7.9Hz, ArH), 7.11-7.18 (8H, m, 8×ArH), 7.65 (1H, dd, J=1.7 and 7.9 Hz,ArH), 7.93 (1H, d, J=1.7 Hz, ArH); ¹³C (125 MHz, CDCl₃) δ 29.1, 29.9,31.9, 32.0, 41.5, 42.4, 60.0, 70.0, 72.6, 95.2, 120.0, 122.7, 127.8,128.4, 128.8, 129.5, 130.7, 131.4, 133.3, 134.7, 136.2, 137.0, 143.4,151.7, 168.3; MS (ES+) 424.3 [M-(OH)C(CH₃)₂CH₂CH₂O]⁻;

Example 17:(3R)-3-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-6-(2-hydroxypropan-2-yl)-3-[(1H-pyrazol-4-yl)methoxy]-2,3-dihydro-1H-isoindol-1-one

Example 17, Step 1: Ethyl1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carboxylate

NaH (80% in oil, 130 mg, 4.3 mmol, 1.5 eq.) was added to4-ethoxycarbonyl-1H-pyrazole (400 mg, 2.86 mmol, 1 eq.) in THF (8 mL),and the mixture stirred at r.t. for 30 min. SEMCl (556 μL, 3.14 mmol,1.1 eq.) was added and the reaction stirred at r.t. for 18 h. Themixture was partitioned between EtOAc (2×30 mL) and water (20 mL), theorganic layers dried (MgSO₄) and the solvent removed in vacuo. Theresidue was purified by MPLC on silica with gradient elution from 5-20%EtOAc/petrol to give the title compound as a clear oil (657 mg, 85%);HRMS found 271.1468 MH+

Example 17, Step 2:(1-((2-(Trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)methanol

LiAIH₄ (1 M in THF, 1.94 mL, 1.94 mmol, 1.5 eq.) was added to ethyl1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carboxylate (350 mg,1.29 mmol) in THF (4 mL) at 0° C., and the mixture was stirred at r.t.for 4 h. Water (74 μL) was added, followed by NaOH (15% aq, 220 μL) andwater (74 μL). The mixture was stirred at r.t. for 1 h, filtered, thesolids washed with EtOAc, and the filtrate evaporated in vacuo to givethe title compound as a clear oil (330 mg, >100%); HRMS calc forC₁₀H₂₁O₂N₂Si, 229.1367, found 229.1361. MH+

Example 17, Step 3:6-Acetyl-2-(4-chlorobenzyl)-3-(4-chlorophenyl)-3-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)methoxy)isoindolin-1-one

Prepared in a similar manner to Preparation 12 using6-acetyl-2-(4-chlorobenzyl)-3-(4-chlorophenyl)-3-hydroxyisoindolin-1-one(Preparation 20) (150 mg, 0.35 mmol, 1 eq.), SOCl₂ (51 μL, 0.70 mmol, 2eq.) and (1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)methanol(161 mg, 0.70 mmol, 2 eq.) The title compound was obtained as a clearglass (105 mg, 47%); HRMS found 636.1830. MH+

Example 17, Step 4:2-(4-Chlorobenzyl)-3-(4-chlorophenyl)-6-(2-hydroxypropan-2-yl)-3-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)methoxy)isoindolin-1-one

Prepared in a similar manner to Example 1 using MeMgCl (151 μL, 3 M inTHF, 0.45 mmol, 1.5 eq.) and ZnCl₂ (8 mg, 0.06 mmol, 0.2 eq.) in THF (1mL), followed by6-acetyl-2-(4-chlorobenzyl)-3-(4-chlorophenyl)-3-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)methoxy)isoindolin-1-one(192 mg, 0.30 mmol, 1 eq). The title compound was obtained as a cleargum (78 mg, 40%); HRMS 652.2145. MH+

Example 17, Step 5:(3R)-3-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-6-(2-hydroxypropan-2-yl)-3-[(1H-pyrazol-4-yl)methoxy]-2,3-dihydro-1H-isoindol-1-one

Et₄NF.H₂O (149 mg, 1.0 mmol, 10 eq.) and 4 A molecular sieves (50 mg)were added to2-(4-chlorobenzyl)-3-(4-chlorophenyl)-6-(2-hydroxypropan-2-yl)-3-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)methoxy)isoindolin-1-one (65 mg, 0.1 mmol) inTHF (2 mL) and the mixture was heated to 65° C. for 3 h, allowed to coolto r.t., and partitioned between EtOAc (25 mL) and water (3×20 mL). Theorganic layer was dried (MgSO₄) and the solvent removed in vacuo to givea white solid (25 mg, 48%). The enantiomers were separated by chiralHPLC (Daicel Chiralpak IA, 250×10 mm i.d., 5 μm, n-heptane: 2-propanol5:1; 4.7 mL/min) to give the title compound (6 mg). ¹H NMR (500 MHz;CDCl₃) └_(H)1.63 (6H, 2×s), 3.66 (1H, d), 3.76 Hz (1H, d), 4.00 (1H, d),4.72 (1H, d), 7.08-7.27 (9H, m), 7.72 (1H, dd), 8.03 (1H, dd); HRMSfound 522.1334. MH+

Example 18:1-({[(1R)-1-(4-chiorophenyl)-2-[(4-chiorophenyl)methyl]-5-(2-hydroxypropan-2-yl)-3-oxo-2,3-dihydro-1H-isoindol-1-yl]oxy}methyl)cyclopropane-1-carbonitrile

Example 18, Step 1: 1-(Hydroxymethyl)cyclopropanecarbonitrile

LiBH₄ (573 mg, 26.3 mmol, 2 eq) was added to ethyl-1-cyanocyclopropanecarboxylate (1.7 mL, 13.15 mmol, 1 eq.) in THF (18 mL) and the mixturewas heated to 50° C. for 18 h. The reaction was cooled to 0° C. andNaHCO₃ (sat'd aq) was added until gas evolution ceased. The mixture wasdiluted with brine (20 mL) and extracted with EtOAc (1×60 mL), DCM (3×60mL) and 10% MeOH/DCM (2×60 mL). The organic extracts were combined,dried (MgSO₄) and the solvent removed in vacuo to give the titlecompound as a clear oil (820 mg, 65%); ¹H NMR (500 MHz; CDCl₃):0.96-1.01 (2H, m), 1.27-1.31 (2H, m), 3.64 (2H, s).

Example 18, Step 2:1-(((5-Bromo-2-(4-chlorobenzyl)-1-(4-chlorophenyl)-3-oxoisoindolin-1-yl)oxy)methyl)cyclopropane-1-carbonitrile

Thionyl chloride (120 μL, 1.64 mmol, 2 eq.) was added to6-bromo-2-(4-chlorobenzyl)-3-(4-chlorophenyl)-3-hydroxyisoindolin-1-one(Preparation 8) (382 mg, 0.82 mmol, 1 eq.) in THF (4 mL) and the mixturewas stirred at r.t. for 4 h. The solvent was removed in vacuo, theresidue re-dissolved in THF (2 mL), cyanoalcohol (Example 18, Step 1;160 mg, 1.64 mmol, 2 eq.) in THF (2 mL) was added and the mixture wasstirred at r.t. for 18 h. The mixture was diluted with EtOAc (2×30 mL)and washed with water. The organic layers were combined, dried overMgSO₄, and the solvent removed in vacuo. The crude mixture was purifiedby MPLC on SiO₂ with gradient elution from 0-2% Et₂O/DCM to give thetitle compound as a clear gum (390 mg, 87%); MS (ES+) 543.3, 545.3[M+H]⁺.

Example 18, Step 3 and 4:1-({[(1R)-1-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-5-(2-hydroxypropan-2-yl)-3-oxo-2,3-dihydro-1H-isoindol-1-yl]oxy}methyl)cyclopropane-1-carbonitrile

Using the product from Example 18, Step 2, The title compound wasprepared by following procedures similar to those described inPreparation 13 and Example 2: 1H NMR (500 MHz; CDCl3): 0.35-0.42 (1H,m), 0.42-0.49 (1H, m), 1.09-1.20 (2H, m), 1.62 (2×3H, 2×s), 2.31 (1H,d), 2.91 (1H, d), 4.02 (1H, d), 4.72 (1H, d), 7.15-7.22 (5H, m),7.25-7.30 (4H, m), 7.74 (1H, dd), 8.00 (1H, d); MS (ES+) 521.4, 523.4[M+H]+.

Example 19:N-{[1-({[(1R)-1-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-5-(2-hydroxypropan-2-yl)-3-oxo-2,3-dihydro-1H-isoindol-1-yl]oxy}methyl)cyclopropyl]methyl}methanesulfonamide

Example 19, Step 1: 1-(((tert-Butyldiphenylsilyl)oxy)methyl)cyclopropanecarbonitrile

1-(Hydroxymethyl)cyclopropanecarbonitrile (1.1 g, 11.3 mmol), TBDPSCl(2.66 mL, 11.3 mmol, 1 eq.), imidazole (926 mg, 13.6 mmol, 1.2 eq.) andDMAP (69 mg, 0.57 mmol, 0.05 eq.) were combined in DCM (15 mL) andstirred at r.t. for 18 h. The mixture was partitioned between EtOAc(2×20 mL) and water (20 mL), washed with brine, dried (MgSO₄) andsolvent removed in vacuo. The residue was purified by MPLC on silicawith gradient elution from 2-40% EtOAc/petrol to give the title compoundas a clear oil (2.05 g, 54%); HRMS calc for C₂₁H₂₉O₁N₂Si, 353.2044,found 353.2034.

Example 19, Step 2:(1-(((tert-Butyldiphenylsilyl)oxy)methyl)cyclopropyl) methanamine

1-(((tert-Butyldiphenylsilyl)oxy)methyl)cyclopropanecarbonitrile (220mg, 0.66 mmol) was dissolved in MeOH (10 mL) and hydrogenated through aRaney nickel catcart on Thales H-cube at 20° C., 20 bar for 3 h, withconstant recycling of the reaction mixture (1 mL/min flow rate). Thesolvent was removed in vacuo and the residue purified by MPLC on silicawith gradient elution from 0-20% MeOH/EtOAc to give the title compoundas a clear gum (78 mg, 46%); ¹H NMR (500 MHz; CDCl₃) 0.30-0.41 (4H, m),1.06 (9H, s), 2.38 (2H, br s), 2.72 (2H, s), 3.57 (2H, s), 7.35-7.46(6H, m), 7.62-7.69 (4H, m).

Example 19, Step 3:N-((1-(((tert-Butyldiphenylsilyl)oxy)methyl)cyclopropyl)methyl)methanesulfonamide

MsCl (120 μL, 1.54 mmol, 1.1 eq.) was added to a mixture of(1-(((tert-butyldiphenylsilyl)oxy)methyl)cyclopropyl) methanamine (480mg, 1.4 mmol, 1 eq.) and Et₃N (236 μL, 1.69 mmol, 1.2 eq.) in DCM (4 mL)at 0° C. and the mixture was stirred at r.t. for 18 h, partitionedbetween DCM (2×30 mL) and water (20 mL), washed with brine, dried overMgSO₄, and the solvent removed in vacuo. The residue was purified byMPLC on SiO₂ with a gradient from 10-35% EtOAc/petrol to give the titlecompound as a white solid (520 mg, 88%); ¹H NMR (500 MHz; CDCl₃)0.36-0.40 (2H, m), 0.49-0.54 (2H, m), 1.08 (9H, s), 2.90 (3H, s), 3.15(2H, d), 3.54 (2H, s), 4.93 (1H, m), 7.36-7.51 (6H, m), 7.62-7.68 (4H,m).

Example 19, Step 4: N-((1-(Hydroxymethyl)cyclopropyl)methyl)methanesulfonamide

N-((1-(((tert-Butyldiphenylsilyl)oxy)methyl)cyclopropyl)methyl)methanesulfonamide (500 mg, 1.2 mmol, 1 eq.) and Et₄NF (197 mg, 1.32mmol, 1.1 eq.) were combined in THF (10 mL) and stirred at r.t. for 2 h.The mixture was diluted with water (10 mL) and brine (10 mL) andextracted with EtOAc (2×20 mL) and DCM (4×20 mL). The organic extractswere combined, dried over MgSO₄, and the solvent removed in vacuo.Purification by MPLC on SiO₂ with a gradient from 70-100% EtOAc/petrolgave the title compound as a clear oil (188 mg, 88%); MS ES− 178.1[M−H]⁻.

Example 19, Step 5:N-((1-(((5-Bromo-2-(4-chlorobenzyl)-1-(4-chlorophenyl)-3-oxoisoindolin-1-yl)oxy)methyl)cyclopropyl)methyl)methanesulfonamide

Thionyl chloride (117 μL, 1.62 mmol, 2 eq.) was added to6-bromo-2-(4-chlorobenzyl)-3-(4-chlorophenyl)-3-hydroxyisoindolin-1-one(Preparation 8) (375 mg, 0.81 mmol, 1 eq.) and DMF (1 drop, cat.) in THF(4 mL) and stirred at r.t. for 4 h. The solvent was removed in vacuo,the residue redissolved in THF (2 mL), and the alcohol in THF (2 mL) wasadded. The mixture was stirred at r.t. for 96 h, partitioned betweenEtOAc (2×30 mL) and water (20 mL). The organic extracts were combined,dried over MgSO₄, and the solvent removed in vacuo. The crude productwas purified by MPLC on SiO₂ with a gradient from 25-50% EtOAc/petrol togive the title compound as a clear gum (385 mg, 76%); MS ES− 523.2[M−H]⁻.

Example 19, Step 6 and 7:N-{[1-({[(1R)-1-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-5-(2-hydroxypropan-2-yl)-3-oxo-2,3-dihydro-1H-isoindol-1-yl]oxy}methyl)cyclopropyl]methyl}methanesulfonamide

Starting from the product obtained in Step 5; Example 19 was preparedusing procedures similar to those described for Preparation 13 andExample 2. ¹H NMR (500 MHz; CDCl₃) 0.08-0.17 (2H, m), 0.38-0.47 (2H, m),1.61 (3H, s), 1.63 (3H, s), 1.83 (1H, s), 2.53 (1H, d), 2.80 (1H, d),2.84-2.93 (4H, m), 3.16 (1H, dd), 4.15 (1H, d), 4.30 (1H, t), 4.59 (1H,d), 7.13-7.19 (5H, m), 7.19-7.27 (4H, m), 7.75 (1H, dd), 8.00 (1H, d);MS ES+ 603.4, 605.3 [M+H]⁺.

Example 20:(3R)-3-(4-chlorophenyl)-2-[(4-ethynylphenyl)methyl]-3-{[1-(hydroxymethyl)cyclopropyl]methoxy}-6-(2-hydroxypropan-2-yl)-2,3-dihydro-1H-isoindol-1-one

Example 20, Step 1:6-Acetyl-3-(4-chlorophenyl)-3-hydroxy-2-(4-((triisopropylsilyl)ethynyl)benzyl)isoindolin-1-one

Prepared in a similar manner to that described in Preparation 8 from:5-acetyl-2-(4-chlorobenzoyl)benzoic acid (Preparation 19) (1 g, 3.303mmol), SOCl₂ (0.48 mL, 6.607 mmol),(4-((triisopropylsilyl)ethynyl)phenyl)methanamine (Preparation 42) (1.14g, 3.964 mmol) and DIPEA (1.27 mL, 7.27 mmol) in THF (20 mL). Purifiedby Biotage using 0-30% EtOAc in petrol as the eluent gave the titlecompound as a pale yellow solid (1.283 g, 68%). MS:[M+H]⁺=456.4.

Example 20, Step 2:6-Acetyl-3-(4-chlorophenyl)-3-((1-(hydroxymethyl)cyclopropyl)methoxy)-2-(4-((triisopropylsilyl)ethynyl)benzyl)isoindolin-1-one

Prepared in a similar manner to that described in Preparation 22 from:6-acetyl-3-(4-chlorophenyl)-3-hydroxy-2-(4-((triisopropylsilyl)ethynyl)benzyl)isoindolin-1-one(400 mg, 0.70 mmol), SOCl₂ (166 mg, 0.10 mL, 1.40 mmol),1,1-bis(hydroxymethyl)cyclopropane (104 mg, 0.14 mL, 1.40 mmol) andK₂CO₃ (194 mg, 1.40 mmol) in THF (1.5 mL). Purified by Biotage using0-40% EtOAc in petrol as the eluent gave the title compound as acolourless oil (205 mg, 45%); 1H NMR (500 MHz, CDCl₃) 0.13-0.17 (2H, m)0.39-0.43 (2H, m), 1.11 (21H, s), 2.67-2.69 (4H, m), 2.77 (1H, d), 3.35(1H, d), 3.50 (1H, d), 4.21 (1H, d), 4.59 (1H, d), 7.12-7.13 (2H, m),7.17-7.26 (5H, m), 7.28 (2H, m), 8.14-8.15 (1H, m), 8.43-8.44 (1H, m).

Example 20, Step 3:3-(4-Chlorophenyl)-3-((1-(hydroxymethyl)cyclopropyl)methoxy)-6-(2-hydroxypropan-2-yl)-2-(4-((triisopropylsilyl)ethynyl)benzyl)isoindolin-1-one

Prepared in a similar manner to that described in Example 1 from:6-acetyl-3-(4-chlorophenyl)-3-((1-(hydroxymethyl)cyclopropyl)methoxy)-2-(4-((triisopropylsilyl)ethynyl)benzyl)isoindolin-1-one(180 mg, 0.27 mmol), Zn(II)Cl₂ (7.5 mg, 0.055 mmol) and MeMgCl (0.23 mL,3.0 M in THF, 0.17 mmol) in THF (1.94 mL). The title product wasobtained as a white solid (148 mg, 82%); 1H NMR (500 MHz, CDCl₃)0.12-0.18 (2H, m), 0.36-0.43 (2H, m), 1.11 (21H, s), 1.61 (3H, s), 1.62(3H, s), 2.66 (1H, d), 2.82 (1H, d), 3.35 (1H, d), 3.48 (1H, d), 4.19(1H, d), 4.57 (1H, d), 7.09-7.13 (3H, m), 7.17-7.21 (4H, m), 7.26-7.28(2H, m), 7.71 (1H, dd), 7.99 (1H, d).

Example 20, Step 4:(3R)-3-(4-chlorophenyl)-2-[(4-ethynylphenyl)methyl]-3-{[1-(hydroxymethyl)cyclopropyl]methoxy}-6-(2-hydroxypropan-2-yl)-2,3-dihydro-1H-isoindol-1-one

Starting from3-(4-chlorophenyl)-3-((1-(hydroxymethyl)cyclopropyl)methoxy)-6-(2-hydroxypropan-2-yl)-2-(4-((triisopropylsilyl)ethynyl)benzyl)isoindolin-1-one,deprotection using a similar procedure to that described in Example 10gave Example 20. 1H NMR (500 MHz, CDCl₃) 0.09-0.18 (2H, m), 0.37-0.42(2H, m), 1.61 (3H, s), 1.62 (3H, s), 2.65 (1H, d), 2.82 (1H, d), 3.04(1H, s), 3.34 (1H, d), 3.47 (1H, d), 4.17 (1H, d), 4.60 (1H, d), 7.11(1H, d), 7.16-7.22 (6H, m), 7.31 (2H, d), 7.72 (1H, dd), 7.99 (1H, d).MS:[M+H]⁺=516.4.

Example 21:(3R)-3-(4-chlorophenyl)-2-[(4-ethynylphenyl)methyl]-4-fluoro-3-{[1-(hydroxymethyl)cyclopropyl]methoxy}-6-(2-hydroxypropan-2-yl)-2,3-dihydro-1H-isoindol-1-one

Example 21. Step 1:6-Bromo-3-(4-chloro-phenyl)-4-fluoro-3-hydroxy-2-{4-[(triisopropylsilanyl)-ethynyl]-benzyl}-2,3-dihydro-isoindol-1-one

The title compound was prepared from5-bromo-2-(4-chloro-benzoyl)-3-fluoro-benzoic acid (7.9 g, 22.2 mmol)and 4-[(triisopropylsilanyl)-ethynyl]-benzylamine (7.0 g, 24.4 mmol) ina similar manner to that described for Preparation 9. 1H NMR (400 MHz,DMSO-d6): 7.84-7.72 (2H, m), 7.59 (1H, s), 7.33-7.20 (6H, m), 7.12 (2H,d), 4.46-4.37 (1H, m), 4.29 (1H, d), 1.13-1.05 (21H, m).

Example 21. Step 2:6-Bromo-3-(4-chloro-phenyl)-4-fluoro-3-(1-hydroxymethyl-cyclopropylmethoxy)-2-{4-[(triisopropylsilanyl)-ethynyl]-benzyl}-2,3-dihydro-isoindol-1-one

The title compound was prepared from6-bromo-3-(4-chloro-phenyl)-4-fluoro-3-hydroxy-2-{4-[(triisopropylsilanyl)-ethynyl]-benzyl}-2,3-dihydro-isoindol-1-one(5.0 g, 7.9 mmol) and (1-hydroxymethyl-cyclopropyl)-methanol (4.1 g,39.9 mmol) in a similar manner to that described for Preparation 10. 1HNMR (400 MHz, DMSO-d6): 7.91 (1H, d), 7.83 (1H, dd), 7.35-7.12 (6H, m),7.03 (2H, d), 4.51-4.27 (3H, m), 3.44-3.33 (2H, m), 2.86 (2H, s), 1.09(21H, s), 0.41-0.26 (2H, m), 0.26-0.10 (2H, m).

Example 21, Step 3:6-Acetyl-3-(4-chloro-phenyl)-2-[4-(3,3-diisopropyl-4-methyl-pent-1-ynyl)-benzyl]-4-fluoro-3-(1-hydroxymethyl-cyclopropylmethoxy)-2,3-dihydro-isoindol-1-one

Pd(PPh₃)₄ (84 mg, 0.07 mmol) and LiCl (178 mg, 4.24 mmol) were added toa solution of6-bromo-3-(4-chloro-phenyl)-4-fluoro-3-(1-hydroxymethyl-cyclopropylmethoxy)-2-{4-[(triisopropylsilanyl)-ethynyl]-benzyl}-2,3-dihydro-isoindol-1-one(1.0 g, 1.4 mmol) in dioxane/toluene (1:1, 20 mL) under N₂ and theresulting solution was degassed for 10 minutes.Tributyl(1-ethoxyvinyl)tin (475 μL, 1.41 mmol) was added and thereaction was stirred at 110° C. for 1.5 hours. The reaction mixture wascooled to room temperature, quenched with NaHCO₃ and extracted withEtOAc. The organic phase was dried over Na₂SO₄, filtered andconcentrated in vacuo. The crude material was columned (gradient 0-50%EtOAc in Petrol) to give 900 mg of a pale yellow solid which wasdissolved in dioxane (10 mL) followed by 2M HCl (6 mL). The solution wasstirred at room temperature for 1 hour, quenched with NaHCO₃ andextracted with DCM. The organic phase was dried over Na₂SO₄, filteredand concentrated in vacuo to give the desired product as a yellow solid.1H NMR (400 MHz, DMSO-d6): 8.21 (1H, d), 7.95 (1H, dd), 7.37-7.10 (6H,m), 7.06 (2H, d), 4.51-4.28 (3H, m), 3.43-3.33 (2H, m), 2.94-2.77 (2H,m), 2.69 (3H, s), 1.08 (21H, s), 0.41-0.25 (2H, m), 0.23-0.10 (2H, m).

Example 21. Step 4:3-(4-Chloro-phenyl)-4-fluoro-3-(1-hydroxymethyl-cyclopropylmethoxy)-6-(1-hydroxy-1-methyl-ethyl)-2-{4-[(triisopropylsilanyl)-ethynyl]-benzyl}-2,3-dihydro-isoindol-1-one

The title compound was prepared from6-acetyl-3-(4-chloro-phenyl)-2-[4-(3,3-diisopropyl-4-methyl-pent-1-ynyl)-benzyl]-4-fluoro-3-(1-hydroxymethyl-cyclopropylmethoxy)-2,3-dihydro-isoindol-1-one(871 mg, 1.29 mmol) in a similar manner to that described for Example 1.¹H NMR (400 MHz, DMSO-d6): 7.80 (1H, d), 7.49 (1H, d), 7.36-7.10 (6H,m), 7.05 (2H, d), 5.36 (1H, s), 4.50-4.25 (3H, m), 3.42-3.32 (2H, m),2.91-2.75 (2H, m), 1.48 (6H, s), 1.09 (21H, s), 0.40-0.25 (2H, m), 0.15(2H, s).

Example 21. Step 5:(3R)-3-(4-chlorophenyl)-2-[(4-ethynylphenyl)methyl]-4-fluoro-3-{[1-(hydroxymethyl)cyclopropyl]methoxy}-6-(2-hydroxypropan-2-yl)-2,3-dihydro-1H-isoindol-1-one

The title compound was prepared by following procedures similar to thosedescribed for Example 11. Purification by preparative chiral HPLC gavethe title compound (173 mg). ¹H NMR (400 MHz, DMSO-d₆): 7.80 (1H, d),7.50 (1H, d), 7.37-7.17 (6H, m), 7.09 (2H, d), 5.36 (1H, s), 4.50-4.35(2H, m), 4.28 (1H, d), 4.11 (1H, s), 3.38 (1H, dd), 3.28 (1H, dd), 2.89(1H, d), 2.77 (1H, d), 1.48 (6H, s), 0.39-0.24 (2H, m), 0.18-0.00 (2H,m). MS:[M+H]⁺=534.

Examples 22 and 23:(3R)-3-(4-chlorophenyl)-6-(1,2-dihydroxypropan-2-yl)-2-[(4-ethynylphenyl)methyl]-4-fluoro-3-{[1-(hydroxymethyl)cyclopropyl]methoxy}-2,3-dihydro-1H-isoindol-1-one

(*Two Isomers at the Position Shown)

Example 22 and Example 23. Step 1:3-(4-Chloro-phenyl)-4-fluoro-3-(1-hydroxymethyl-cyclopropylmethoxy)-6-isopropenyl-2-{4-[(triisopropylsilanyl)-ethynyl]-benzyl}-2,3-dihydro-isoindol-1-one

The title compound was prepared in a similar fashion to Preparation 13.¹H NMR (400 MHz, DMSO-d6): 7.79 (1H, d), 7.63-7.55 (1H, m), 7.34-7.09(6H, m), 7.05 (2H, d), 5.68 (1H, s), 5.30 (1H, s), 4.49-4.28 (3H, m),3.36 (2H, d), 2.87 (2H, s), 2.17 (3H, s), 1.16-1.03 (21H, m), 0.42-0.26(2H, m), 0.17 (2H, d).

Example 22 and Example 23. Step 2:3-(4-Chloro-phenyl)-6-(1,2-dihydroxy-1-methyl-ethyl)-4-fluoro-3-(1-hydroxymethyl-cyclopropylmethoxy)-2-{4-[(triisopropylsilanyl)-ethynyl]-benzyl}-2,3-dihydro-isoindol-1-one

The title compound was prepared by using a similar procedure to thatdescribed in Example 27 Step 4. ¹H NMR (400 MHz, DMSO-d6): 7.79 (1H,dd), 7.50-7.42 (1H, m), 7.35-7.10 (6H, m), 7.05 (2H, d), 5.28 (1H, s),4.86-4.79 (1H, m), 4.42 (1H, t), 4.35 (2H, s), 3.54-3.40 (2H, m), 3.36(2H, dd), 2.93-2.78 (2H, m), 2.55-2.40 (25H, m), 1.43 (3H, s), 1.14-1.03(21H, m), 0.40-0.27 (2H, m), 0.21-0.09 (2H, m).

Example 22 and Example 23. Step 3:(3R)-3-(4-chlorophenyl)-6-(1,2-dihydroxypropan-2-yl)-2-[(4-ethynylphenyl)methyl]-4-fluoro-3-{[1-(hydroxymethyl)cyclopropyl]methoxy}-2,3-dihydro-1H-isoindol-1-one(Isomer A and B)

The title compounds were prepared from3-(4-chloro-phenyl)-6-(1,2-dihydroxy-1-methyl-ethyl)-4-fluoro-3-(1-hydroxymethyl-cyclopropylmethoxy)-2-{4-[(triisopropylsilanyl)-ethynyl]-benzyl}-2,3-dihydro-isoindol-1-one(1.0 g, 1.4 mmol) in a similar manner to that described in Example 10.Purification by preparative chiral HPLC gave:—

Example 22 (*isomer 1): 1H NMR (400 MHz, DMSO-d6): 7.78 (1H, s), 7.47(1H, d), 7.36-7.16 (6H, m), 7.09 (2H, d), 5.29 (1H, s), 4.82 (1H, t),4.50-4.32 (2H, m), 4.28 (1H, d), 4.12 (1H, s), 3.52-3.34 (3H, m), 3.29(1H, dd), 2.89 (1H, d), 2.78 (1H, d), 1.43 (3H, s), 0.38-0.25 (2H, m),0.17-0.00 (2H, m). MS: [M−H]⁻=548.

Example 23)*isomer 2): 1H NMR (400 MHz, DMSO-d6): 7.79 (1H, d), 7.46(1H, d), 7.36-7.13 (6H, m), 7.09 (2H, d), 5.42-5.12 (1H, m), 4.98-4.60(1H, m), 4.41 (1H, d), 4.29 (1H, d), 4.12 (1H, s), 3.50 (1H, d), 3.44(1H, d), 3.38 (2H, d), 3.29 (1H, d), 2.89 (1H, d), 2.79 (1H, d), 1.43(3H, s), 0.39-0.29 (2H, m), 0.18-0.00 (2H, m)

Example 24:4-{[(1R)-1-(4-chlorophenyl)-7-fluoro-1-({1-[hydroxy(²H₂)methyl]cyclopropyl}(²H₂)methoxy)-5-(2-hydroxypropan-2-yl)-3-oxo-2,3-dihydro-1H-isoindol-2-yl]methyl}benzonitrile

Example 24. Step 1:4-[5-Bromo-1-(4-chloro-phenyl)-7-fluoro-1-hydroxy-3-oxo-1,3-dihydro-isoindol-2-ylmethyl]-benzonitrile

The title compound was prepared from5-bromo-2-(4-chloro-benzoyl)-3-fluoro-benzoic acid (4.0 g, 11.2 mmol)and 4-aminomethyl-benzonitrile hydrochloride (2.0 g, 11.2 mmol) in asimilar manner to that described for Preparation 9 MS: [M−H]⁻=470.

Example 24. Step 2:4-{[5-Bromo-1-(4-chlorophenyl)-7-fluoro-1-({1-[hydroxy(2H2)methyl]cyclopropyl}(2H2)methoxy)-3-oxo-2,3-dihydro-1H-isoindol-2-yl]methyl}benzonitrile

The title compound was prepared from4-[5-bromo-1-(4-chloro-phenyl)-7-fluoro-1-hydroxy-3-oxo-1,3-dihydro-isoindol-2-ylmethyl]-benzonitrile(1.0 g, 2.1 mmol) and {1-[hydroxy(²H₂)methyl]cyclopropyl}(²H₂)methanol(890 mg, 8.4 mmol) in a similar manner to that described for Preparation10 MS: [M−H]⁻=558.

Example 24. Step 3:4-{[1-(4-Chlorophenyl)-7-fluoro-1-({1-[hydroxy(2H2)methyl]cyclopropyl}(2H2)methoxy)-3-oxo-5-(prop-1-en-2-yl)-2,3-dihydro-1H-isoindol-2-yl]methyl}benzonitrile

The title compound was prepared from4-{[5-bromo-1-(4-chlorophenyl)-7-fluoro-1-({1-[hydroxy(²H²)methyl]cyclopropyl}(²H²)methoxy)-3-oxo-2,3-dihydro-1H-isoindol-2-yl]methyl}benzonitrile(750 mg, 1.33 mmol) in a similar manner to that described in Preparation13. MS: [M−H]⁻=519.

Example 24. Step 4:4-{[(1R)-1-(4-chlorophenyl)-7-fluoro-1-({1-[hydroxy(²H²)methyl]cyclopropyl}(²H₂)methoxy)-5-(2-hydroxypropan-2-yl)-3-oxo-2,3-dihydro-1H-isoindol-2-yl]methyl}benzonitrile

The title compound was prepared from4-{[1-(4-chlorophenyl)-7-fluoro-1-({1-[hydroxy(2H2)methyl]cyclopropyl}(2H2)methoxy)-3-oxo-5-(prop-1-en-2-yl)-2,3-dihydro-1H-isoindol-2-yl]methyl}benzonitrile(660 mg, 1.27 mmol) in a similar manner to that described for Example 2.1H NMR (400 MHz, DMSO-d6): 7.81 (1H, d), 7.61 (2H, d), 7.57-7.46 (1H,m), 7.34-7.15 (6H, m), 5.37 (1H, s), 4.44 (2H, s), 4.40-4.30 (1H, m),1.48 (6H, s), 0.39-0.26 (2H, m), 0.21-0.03 (2H, m). MS: [M−H]⁻=537.

Example 25:4-{[(1R)-1-(4-chlorophenyl)-1-{[1-(hydroxymethyl)cyclopropyl]methoxy}-5-(2-hydroxypropan-2-yl)-3-oxo-2,3-dihydro-1H-isoindol-2-yl]methyl}benzonitrile

Example 25, Step 1:6-Acetyl-2-(4-bromobenzyl)-3-(4-chlorophenyl)-3-hydroxyisoindolin-1-one

Prepared in a similar manner to that described in Preparation 9 from:5-acetyl-2-(4-chlorobenzoyl)benzoic acid. MS:[M−H]⁻=470.2.

Example 25, Step 2:6-Acetyl-2-(4-bromobenzyl)-3-(4-chlorophenyl)-3-((1-(hydroxymethyl)cyclopropyl)methoxy)isoindolin-1-one

Prepared in a similar manner to that described in Preparation 22 from:6-acetyl-2-(4-bromobenzyl)-3-(4-chlorophenyl)-3-hydroxyisoindolin-1-one.1H NMR (500 MHz, CDCl₃) 0.09-0.18 (2H, m), 0.40-0.44 (2H, m), 2.67-2.69(4H, m), 2.78 (1H, d), 3.36 (1H, d), 3.50 (1H, d), 4.19 (1H, d), 4.55(1H, d), 7.07-7.08 (2H, m), 7.17-7.18 (2H, m), 7.21-7.26 (3H, m),7.30-7.32 (2H, m), 8.14 (1H, dd), 8.43 (1H, d).

Example 25, Step 3:2-(4-Bromobenzyl)-3-(4-chlorophenyl)-3-((1-(hydroxymethyl)cyclopropyl)methoxy)-6-(2-hydroxypropan-2-yl)isoindolin-1-one

Prepared in a similar manner to that described in Example 1 from:6-acetyl-2-(4-bromobenzyl)-3-(4-chlorophenyl)-3-((1-(hydroxymethyl)cyclopropyl)methoxy)isoindolin-1-on.1H NMR (500 MHz, CDCl₃) 0.12-0.20 (2H, m), 0.39-0.44 (2H, m), 1.61 (3H,s), 1.62 (3H, s), 2.66 (1H, d), 2.83 (1H, d), 3.37 (1H, d), 3.48 (1H,d), 4.17 (1H, d), 4.52 (1H, d), 7.07-7.11 (3H, m), 7.17-7.22 (4H, m),7.29-2.31 (2H, m), 7.72 (1H, dd), 7.99 (1H, d).

Example 25, Step 4:4-{[(1R)-1-(4-chlorophenyl)-1-{[1-(hydroxymethyl)cyclopropyl]methoxy}-5-(2-hydroxypropan-2-yl)-3-oxo-2,3-dihydro-1H-isoindol-2-yl]methyl}benzonitrile

In a microwave vial, a mixture of2-(4-bromobenzyl)-3-(4-chlorophenyl)-3-((1-(hydroxymethyl)cyclopropyl)methoxy)-6-(2-hydroxypropan-2-yl)isoindolin-1-one(140 mg, 0.25 mmol), zinc powder (3.3 mg, 0.05 mmol), Pd(OAc)₂ (11.2 mg,0.05 mmol), rac-2-(di-tert-butylphosphino)-1,1′-binapthyl (39.8 mg, 0.10mmol) and Zn(CN)₂ (32.3 mg, 0.275 mmol) in MeCN (1.5 mL) was degassedunder N₂ for 20 min then heated to 120° C. for 1 h. The reaction wascooled to RT, diluted with EtOAc (25 mL) and filtered through Celite.The organic layer was washed with water (100 mL), brine (100 mL), driedover Na₂SO₄ and concentrated under vacuum. Purified by Biotage 0-50%EtOAc in petrol as the eluent then semi-preparative HPLC gave theracemic mixture as a white solid (55 mg, 43%). Purification bypreparative chiral HPLC gave the title compound as a white solid (24.4mg). 1H NMR (500 MHz, CD₃OD-d₄) 0.16-0.29 (2H, m), 0.41-0.46 (2H, m),1.58 (6H, s), 2.84-2.90 (2H, m), 3.48-3.56 (2H, m), 4.44 (1H, d), 4.64(1H, d), 7.15-7.21 (5H, m), 7.26-7.28 (2H, m), 7.47-7.49 (2H, m), 7.78(1H, dd), 8.04 (1H, d). MS:[M+H]⁺=517.4.

Example 26:(3R)-3-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-6-(2-hydroxypropan-2-yl)-3-[(3-methyloxetan-3-yl)methoxy]-2,3-dihydro-1H-isoindol-1-one

Example 26, Step 1: 2-(Bromomethyl)-2-methylpropane-1,3-diol

At −10° C., to a solution of 3-methyl-3-oxetanemethanol (1.00 g, 9.8mmol) in THF (12.3 mL) was added aqueous HBr (48 wt %, 3.9 mL) and theresulting yellow/brown solution was stirred for 4 h at −10° C. then atRT for 12 h. The mixture was diluted with brine (100 mL) and extractedinto Et₂O (4×100 mL). The combined organic layers were dried over Na₂SO₄and concentrated under vacuum to give the title compound as a whitesolid (1.36 g, 76%); 1H NMR (500 MHz, CDCl₃) 0.91 (3H, s), 2.73 (2H, s),3.53 (2H, s), 3.65 (4H, s).

Example 26, Step 2:6-Bromo-3-(3-bromo-2-(hydroxymethyl)-2-methylpropoxy)-2-(4-chlorobenzyl)-3-(4-chlorophenyl)isoindolin-1-one

Prepared in a similar manner to that described in Preparation 22 from:6-bromo-2-(4-chlorobenzyl)-3-(4-chlorophenyl)-3-hydroxyisoindolin-1-one(Preparation 9) (635 mg, 1.37 mmol), SOCl₂ (325 mg, 0.20 mL, 2.73 mmol),2-(bromomethyl)-2-methylpropane-1,3-diol (500 mg, 2.73 mmol) and K₂CO₃(377 mg, 2.73 mmol) in THF (2.9 mL). Purified by Biotage using 0-20%EtOAc in petrol as the eluent gave the title compound as a white solid(302 mg, 35%). MS:[M+H]⁺=628.3.

Example 26, Step 3:6-Bromo-2-(4-chlorobenzyl)-3-(4-chlorophenyl)-3-((3-methyloxetan-3-yl)methoxy)isoindolin-1-one

To a solution of6-bromo-3-(3-bromo-2-(hydroxymethyl)-2-methylpropoxy)-2-(4-chlorobenzyl)-3-(4-chlorophenyl)isoindolin-1-one(820 mg, 1.31 mmol) in EtOH (28 mL) was added KOH (88 mg, 1.57 mmol) andthe mixture heated at reflux for 6 h then cooled to RT. The reaction wasdiluted with water (50 mL) and acidified to pH 6 with 1.0 M aqueous HClsolution. The reaction was extracted into EtOAc (3×40 mL), washed withbrine, dried over MgSO₄ and concentrated under vacuum. Purified byBiotage using 0-20% EtOAc in petrol as the eluent gave the titlecompound as a white solid (516 mg, 72%). 1H NMR (500 MHz, CDCl₃) 1.13(3H, s), 2.75-2.81 (2H, m), 4.16-4.22 (2H, m), 4.26-4.27 (1H, m),4.32-4.34 (2H, m), 4.51 (1H, d), 6.97 (1H, d), 7.07-7.09 (2H, m),7.13-7.14 (2H, m), 7.17-7.23 (4H, m), 7.65 (1H, dd), 8.06 (1H, d).

Example 26, Step 4:2-(4-Chlorobenzyl)-3-(4-chlorophenyl)-3-((3-methyloxetan-3-yl)methoxy)-6-(prop-1-en-2-yl)isoindolin-1-one

Prepared in a similar manner to that described in Preparation 13 from:6-bromo-2-(4-chlorobenzyl)-3-(4-chlorophenyl)-3-((3-methyloxetan-3-yl)methoxy)isoindolin-1-one.1H NMR (500 MHz, CDCl₃) 1.13 (3H, s), 2.20 (3H, s), 2.79 (2H, s),4.16-4.27 (3H, m), 4.32-4.35 (2H, m), 4.52-4.55 (1H, m), 5.21 (1H, s),5.48 (1H, s), 7.04 (1H, d), 7.09-7.14 (4H, m), 7.17-7.23 (4H, m), 7.63(1H, dd), 8.00 (1H, d).

Example 26, Step 5:6-Acetyl-2-(4-chlorobenzyl)-3-(4-chlorophenyl)-3-((3-methyloxetan-3-yl)methoxy)isoindolin-1-one

Prepared in a similar manner to that described in Preparation 15 from:2-(4-chlorobenzyl)-3-(4-chlorophenyl)-3-((3-methyloxetan-3-yl)methoxy)-6-(prop-1-en-2-yl)isoindolin-1-one.MS:[M+H]⁺=510.4.

Example 26, Step 6:(3R)-3-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-6-(2-hydroxypropan-2-yl)-3-[(3-methyloxetan-3-yl)methoxy]-2,3-dihydro-1H-isoindol-1-one

Prepared in a similar manner to that described in Example 1 from:6-acetyl-2-(4-chlorobenzyl)-3-(4-chlorophenyl)-3-((3-methyloxetan-3-yl)methoxy)isoindolin-1-one.1H NMR (500 MHz, CDCl₃) 1.13 (3H, s), 1.63 (3H, s), 1.64 (3H, s), 2.78(2H, s), 4.16-4.22 (2H, m), 4.25-4.27 (1H, m), 4.34-4.36 (2H, m), 4.54(1H, d), 7.60 (1H, d), 7.10-7.14 (4H, m), 7.19-7.22 (4H, m), 7.73 (1H,dd), 8.02 (1H, d). MS:[M+H]⁺=526.4.

Examples 27 and 28:4-{[(1R)-1-(4-chlorophenyl)-5-(1,2-dihydroxypropan-2-yl)-1-{[1-(hydroxymethyl)cyclopropyl]methoxy}-3-oxo-2,3-dihydro-1H-isoindol-2-yl]methyl}benzonitrile

(*Both Isomers at Position Shown)

Example 27 and Example 28, Step 2 and 3:4-((1-(4-Chlorophenyl)-hydroxy-((1-(hydroxymethyl)cyclopropyl)methoxy)-3-oxo-5-(prop-1-en-2-yl)isoindolin-2-yl)methyl)benzonitrile

Prepared in a similar manner to that described in Preparation 9 from:5-bromo-2-(4-chlorobenzoyl)benzoic acid and 4-(aminomethyl)benzonitrile.MS:[M−H]⁻=453.1.

Example 27 and Example 28, Step 2 and 3:4-((1-(4-Chlorophenyl)-1-((1-(hydroxymethyl)cyclopropyl)methoxy)-3-oxo-5-(prop-1-en-2-yl)isoindolin-2-yl)methyl)benzonitrile

Starting from:4-((5-bromo-1-(4-chlorophenyl)-1-hydroxy-3-oxoisoindolin-2-yl)methyl)benzonitrile,the title compound was prepared in a similar manner to that described inPreparation 12 and 13. 1H NMR (500 MHz, CD₃OD) 0.19-0.27 (2H, m),0.41-0.46 (2H, m), 2.21 (3H, s), 2.85-2.91 (2H, m), 3.49-3.56 (2H, m),4.45 (1H, d), 4.64 (1H, d), 5.23 (1H, s), 5.51 (1H, s), 7.15-7.22 (5H,m), 7.26-7.28 (2H, m), 7.47-7.48 (2H, m), 7.76 (1H, dd), 7.99 (1H, d).

Example 27 and Example 28, Step 4:4-{[(1R)-1-(4-chlorophenyl)-5-(1,2-dihydroxypropan-2-yl)-1-{[1-(hydroxymethyl)cyclopropyl]methoxy}-3-oxo-2,3-dihydro-1H-isoindol-2-yl]methyl}benzonitrile

At 0° C., to a solution of tert-butanol/water (8.91 mL/8.91 mL) wasadded AD-mix-3 (2.49 g) followed by portion wise addition of4-((1-(4-chlorophenyl)-1-((1-(hydroxymethyl)cyclopropyl)methoxy)-3-oxo-5-(prop-1-en-2-yl)isoindolin-2-yl)methyl)benzonitrile(900 mg, 1.80 mmol) and the resulting mixture was stirred at 0° C. for48 h. Na₂SO₃ (0.98 g, 7.78 mmol) was added and the reaction warmed to RTand diluted with water (50 mL). The reaction was extracted with EtOAc(2×50 mL), dried over MgSO₄ and concentrated under vacuum. Purified byBiotage using 0-100% EtOAc in petrol as the eluent gave adiastereoisomeric mixture of product (177 mg, 18%). Chiral HPLC gave thetitle compounds.

Example 27 (*isomer 1): 1H NMR (500 MHz, CDCl₃) 0.13-0.21 (2H, m),0.42-0.46 (2H, m), 1.58 (3H, s), 2.64 (1H, s), 2.72 (1H, d), 2.88 (1H,d), 3.40 (1H, d), 3.51 (1H, d), 3.71 (1H, d), 3.82 (1H, d), 4.41 (1H,d), 4.50 (1H, d), 7.14-7.18 (5H, m), 7.26-7.28 (2H, m), 7.44-7.46 (2H,m), 7.72 (1H, dd), 7.99 (1H, d). MS:[M+H]⁺=533.4.

Example 28 (*isomers 2): 1H NMR (500 MHz, CDCl₃) 0.13-0.21 (2H, m),0.42-0.47 (2H, m), 1.59 (3H, s), 2.64 (1H, s), 2.73 (1H, d), 2.86 (1H,d), 3.41 (1H, d), 3.51 (1H, d), 3.70 (1H, d), 3.81 (1H, d), 4.41 (1H,d), 4.50 (1H, d), 7.14-7.18 (5H, m), 7.27-7.28 (2H, m), 7.44-7.46 (2H,m), 7.72 (1H, dd), 7.98 (1H, d). MS:[M+H]⁺=533.4.

Example 29:(3R)-3-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-3-[(1-hydroxycyclopropyl)methoxy]-6-(2-hydroxypropan-2-yl)-2,3-dihydro-1H-isoindol-1-one

Example 29, Step 1:6-Acetyl-3-((1-((tert-butyldiphenylsilyl)oxy)cyclopropyl)methoxy)-2-(4-chlorobenzyl)-3-(4-chlorophenyl)isoindolin-1-one

Prepared in a similar manner to that described in Preparation 12 from:6-acetyl-2-(4-chlorobenzyl)-3-(4-chlorophenyl)-3-hydroxyisoindolin-1-one(Preparation 20) and(1-((tert-butyldiphenylsilyl)oxy)cyclopropyl)methanol). 1H NMR (500 MHz,CDCl₃) 0.07-0.12 (2H, m), 0.66-0.75 (2H, m), 0.99 (9H, s), 2.57 (1H, d),2.67 (3H, s), 2.76 (1H, d), 4.24 (2H, s), 6.83 (1H, d), 6.97-6.98 (2H,m), 7.06-7.14 (5H, m), 7.25-7.31 (5H, m), 7.37-7.40 (2H, m), 7.56-7.58(2H, m), 7.65-7.66 (2H, m), 7.99 (1H, dd), 8.34 (1H, d).

Example 29, Step 2:3-((1-((tert-Butyldiphenylsilyl)oxy)cyclopropyl)methoxy)-2-(4-chlorobenzyl)-3-(4-chlorophenyl)-6-(2-hydroxypropan-2-yl)isoindolin-1-one

Prepared in a similar manner to that described in Example 1. 1H NMR (500MHz, CDCl₃) 0.05-0.11 (2H, m), 0.62-0.72 (2H, m), 1.00 (9H, s), 1.61(6H, s), 2.56 (1H, d), 2.84-2.86 (1H, m), 4.20-4.27 (2H, m), 6.75-6.77(1H, m), 6.96-6.98 (2H, m), 7.04-7.06 (2H, m), 7.10-7.13 (4H, m),7.28-7.32 (4H, m), 7.37-7.41 (2H, m), 7.57-7.61 (3H, m), 7.66-7.68 (2H,m), 7.91 (1H, d).

Example 29, Step 3:(3R)-3-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-3-[(1-hydroxycyclopropyl)methoxy]-6-(2-hydroxypropan-2-yl)-2,3-dihydro-1H-isoindol-1-one

Deprotection in a similar manner to that described for Example 10 gaveExample 29. 1H NMR (500 MHz, CDCl₃) 0.19-0.26 (2H, m), 0.70-0.76 (2H,m), 1.61-0.62 (6H, m), 2.71 (1H, d), 2.94 (1H, d), 4.20 (1H, d), 4.54(1H, d), 7.10 (1H, d), 7.13 (4H, s), 7.20-7.24 (4H, m), 7.71 (1H, dd),7.99 (1H, d). MS:[M+H]⁺=512.4.

Example 30:2-{[(1R)-1-(4-Chlorophenyl)-2-[(4-chlorophenyl)methyl]-5-(2-hydroxypropan-2-yl)-3-oxo-2,3-dihydro-1H-isoindol-1-yl]oxy}-N,N-dimethylacetamide

Example 30, Step 1: Methyl2-((5-bromo-2-(4-chlorobenzyl)-1-(4-chlorophenyl)-3-oxoisoindolin-1-yl)oxy)acetate

Using methyl glycolate, the title compound was prepared using aprocedure similar to that described for Preparation 10. MS: [M-C₃H₅O₃]⁺446.

Example 30, Step 2:2-((5-Bromo-2-(4-chlorobenzyl)-1-(4-chlorophenyl)-3-oxoisoindolin-1-yl)oxy)-N,N-dimethylacetamide

Methyl2-((5-bromo-2-(4-chlorobenzyl)-1-(4-chlorophenyl)-3-oxoisoindolin-1-yl)oxy)acetate(756 mg, 1.41 mmol) and 40% aqueous in water dimethylamine (7.6 mL) weremixed and stirred at room temperature for 6.5 h. The solvent was removedin vacuo and FCC [dichloromethane-methanol (100:0)→(94:6)] of the cruderesidue afforded2-((5-bromo-2-(4-chlorobenzyl)-1-(4-chlorophenyl)-3-oxoisoindolin-1-yl)oxy)-N,N-dimethylacetamide(524 mg, 68%) as a white foam. MS: [M-C₄H₈NO₂]⁺ 446.

Example 30, Step 3:(R)-2-((2-(4-chlorobenzyl)-1-(4-chlorophenyl)-5-(2-hydroxypropan-2-yl)-3-oxoisoindolin-1-yl)oxy)-N,N-dimethylacetamide

The title compound was prepared using similar procedures to thosedescribed in Preparation 13 and Example 2. ¹H NMR (500 MHz, CDCl₃): 7.94(1H, d, 7-H), 7.62 (1H, dd, ArH), 7.35-7.30 (2H, m, 2×ArH), 7.24-7.18(4H, m, 4×ArH), 7.12-7.07 (3H, m, 3×ArH), 4.74 (1H, d, NC—H′), 3.87 (1H,d, NC—H), 3.20 (1H, d, 4′-H′), 3.08 (1H, d, 4′-H), 2.76 (3H, s, NCH₃),2.37 (3H, s, NCH₃) and 1.56-1.52 (6H, m, 2×CH₃). MS: [M-C₄H₈NO₂]⁺ 424.

Example 31:(3R)-3-(4-Chlorophenyl)-2-[(4-chlorophenyl)methyl]-6-(2-hydroxypropan-2-yl)-3-{[1-(methoxymethyl)cyclopropyl]methoxy}-2,3-dihydro-1H-isoindol-1-one

Example 31, Step 1:2-(4-Chlorobenzyl)-3-(4-chlorophenyl)-3-((1-(methoxymethyl)cyclopropyl)methoxy)-6-(prop-1-en-2-yl)isoindolin-1-one

To a solution of2-(4-chlorobenzyl)-3-(4-chlorophenyl)-3-((1-(hydroxymethyl)cyclopropyl)methoxy)-6-(prop-1-en-2-yl)isoindolin-1-one,Preparation 13 (318 mg, 0.625 mmol) in anhydrous THF (3 mL) undernitrogen, was added ^(t)BuOK (140 mg, 1.25 mmol) at room temperature andthe mixture stirred for 1 h before cooling to 0° C. MeI (0.08 mL, 1.25mol) in anhydrous THF (1 mL) was added dropwise and stirred for 3.5 h.Diluted with EtOAc (10 mL) and washed with water (2×20 mL), brine (20mL), dried over anhydrous Na₂SO₄, filtered and the solvent removed nvacuo. FCC [petrol-ethyl acetate (100:0)→(80:20)] of the crude residueafforded2-(4-chlorobenzyl)-3-(4-chlorophenyl)-3-((1-(methoxymethyl)cyclopropyl)methoxy)-6-(prop-1-en-2-yl)isoindolin-1-one(278 mg, 85%) as a colourless gum. MS: [C₆H₁₁O₂]⁺ 406.

Example 31, Step 2:(R)-2-(4-Chlorobenzyl)-3-(4-chlorophenyl)-6-(2-hydroxypropan-2-yl)-3-((1-(methoxymethyl)cyclopropyl)methoxy)isoindolin-1-one

The title compound was prepared using similar procedures to thosedescribed for Example 2. ¹H NMR (500 MHz, CDCl₃) 8.00 (1H, m, 7-H), 7.73(1H, dd, ArH), 7.24-7.17 (4H, m, 4×ArH) 7.16-7.10 (4H, m, 4×ArH), 7.08(1H, d, ArH), 4.46 (1H, d, NC—H′), 4.30 (1H, d, NC—H), 3.43 (1H, d,4′-H′), 3.31 (3H, s, OCH₃), 3.16 (1H, d, 4′-H), 2.88 (1H, d, 2′-H′),2.61 (1H, d, 2′-H), 1.67-1.62 (6H, m, 2×CH₃), 0.45-0.38 (2H, m,Cy-Py-H₂) and 0.25-0.15 (2H, m, Cy-Py-H). MS: [M-C₆H₁₁O₂]⁺ 424.

Example 32:(3R)-3-(4-Chlorophenyl)-2-[(4-chlorophenyl)methyl]-3-{[1-(hydroxymethyl)cyclobutyl]methoxy}-6-(2-hydroxypropan-2-yl)-2,3-dihydro-1H-isoindol-1-one

Example 32, Step 1: Cyclobutane-1,1-diyldimethanol

To a solution of diethyl-1,1-cyclobutanedicarboxylate (1.00 g, 4.99mmol) in anhydrous THF (13 mL) at 0° C. was added LiBH₄ (239 mg, 11.0mmol) portionwise over 10 min and then stirred for further 10 min beforeheating to 60° C. for 2 h. The reaction mixture was cooled to roomtemperature and then to 0° C. Water (2.5 mL) was added cautiously,followed by 1 M HCl until gas evolution ceased, and then neutralisedwith sat. sol. NaOH. Extracted with EtOAc (3×10 mL) and then combined.To the aqueous layer was added brine (5 mL) and then extracted withEtOAc (2×10 mL). The combined organic phases were washed with brine (15mL), dried (Na₂SO₄), filtered and concentrated in vacuo to give thetitle compound as a colourless thick oil (523 mg, 90%), which was usedwithout purification. ¹H NMR (500 MHz, CDCl₃) 3.75 (4H, s, 2×HC₂OH),2.32 (2H, br s, 2×OH), 1.96-1.90 (2H, m, H-3) and 1.80-1.77 (4H, m, H-2,H-4).

Example 32, Step 2:(R)-2-(4-chlorobenzyl)-3-(4-chlorophenyl)-3-((1-(hydroxymethyl)cyclobutyl)methoxy)-6-(2-hydroxypropan-2-yl)isoindolin-1-one

Starting from Preparation 8, the title compound was prepared usingprocedures similar to those described in Preparation 10, Preparation 13and Example 2. ¹H NMR (500 MHz, CDCl₃) 8.01 (1H, d, 7-H), 7.72 (1H, dd,ArH) 7.21-7.11 (8H, m, 8×ArH), 7.08 (1H, d, ArH), 4.52 (1H, d, NC—H′),4.23 (1H, d, NC—H), 3.53 (2H, d, OCH₂), 2.88 (1H, d, CH₂OH), 2.79 (1H,d, CH₂OH) and 1.86-1.51 (12H, m, 2×CH₃ and 3×CH₂). MS: [M-C₆H₁₁O₂]⁺ 424.

Example 33:5-chloro-2-{[(1R)-1-(4-chlorophenyl)-1-{[1-(hydroxymethyl)cyclopropyl]methoxy}-5-(2-hydroxypropan-2-yl)-3-oxo-2,3-dihydro-1H-isoindol-2-yl]methyl}benzoicacid

Example 33, Step 1; (2-Bromo-4-chlorophenyl)methanamine

To a solution of 2-bromo-4-chlorobenzonitrile (500 mg, 2.3 mmol), in dryTHF (50 mL) was added slowly borane-THF complex (1 M, 12 mL, 11.5 mmol)at 0° C. before refluxing for 1 h. After cooling down, 1 M HCl in MeOH(20 mL) was charged slowly with ice cooling. The solvent was removed byconcentration in vacuo before water (0.61 mmol/mL to benzonitrile) wascharged, then washed by Et₂O (0.61 mmol/mL to benzonitrile) beforebasifying with 2 M NaOH solution to pH 12. Et₂O (15 mL) was added andthe mixture was washed with water (3×15 mL) and brine (1 mL). Theorganic phase was dried (MgSO₄) and concentrated in vacuo to give ayellow oil (345 mg, 68%). LCMS (ESI⁺) m/z=220.1 [M+H]⁺.

Example 33, Step 2;6-Acetyl-2-(2-bromo-4-chlorobenzyl)-3-(4-chlorophenyl)-3-hydroxyisoindolin-1-one

The title compound was prepared using procedures similar to thosedescribed for Preparation 9. LCMS (ESI⁻) m/z=502.1 [M−H]⁻

Example 33, Step 3;6-Acetyl-2-(2-bromo-4-chlorobenzyl)-3-(4-chlorophenyl)-3-((1-(hydroxymethyl)cyclopropyl)methoxy)isoindolin-1-one

The title compound was prepared using procedures similar to thosedescribed for Preparation 10. LCMS (ESI⁺) m/z=588.3 [M+H]⁺.

Example 33, Step 4;6-Acetyl-2-(2-bromo-4-chlorobenzyl)-3-((1-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)methoxy)-3-(4-chlorophenyl)isoindolin-1-one

The title compound was prepared using procedures similar to thosedescribed for Preparation 29. LCMS (ESI⁺) m/z=486.2 [M]⁺.

Example 33, Step 5,2-((5-Acetyl-1-((1-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)methoxy)-1-(4-chlorophenyl)-3-oxoisoindolin-2-yl)methyl)-5-chlorobenzoicacid

To a solution of the previous compound (306 mg, 0.44 mmol) in dry DMF(4.0 mL) was added Xantphos (104 mg, 0.18 mmol), Pd(OAc)₂ (20 mg, 0.09mmol), HCOOLi.H₂O (122 mg, 1.74 mmol) and Et₃N (0.25 mL, 1.74 mmol)before degassing for 15 mins, and then Ac₂O (0.17 mL, 1.74 mmol) wasintroduced before microwave for 30 mins at 140° C. The mixture was gonethrough a plug of Celite, EtOAc (30 mL) was added and the mixture waswashed with water (3×30 mL) and brine (20 mL). The organic phase wasdried (MgSO₄) and concentrated in vacuo. Chromatography (silica; EtOAcwith 0.1% acetic acid, petrol 20-80%) gave a greasy solid (78 mg, 43%).LCMS (ESI⁻) m/z=666.3 [M−H]⁻.

Example 33, Step 6;2-((1-((1-(((tert-Butyldimethylsilyl)oxy)methyl)cyclopropyl)methoxy)-1-(4-chlorophenyl)-5-(2-hydroxypropan-2-yl)-3-oxoisoindolin-2-yl)methyl)-5-chlorobenzoicacid

The title compound was prepared using procedures similar to thosedescribed for Example 1. LCMS (ESI⁻) m/z=682.4 [M−H]⁻.

Example 33, Step 7:5-chloro-2-{[(1R)-1-(4-chlorophenyl)-1-{[1-(hydroxymethyl)cyclopropyl]methoxy}-5-(2-hydroxypropan-2-yl)-3-oxo-2,3-dihydro-1H-isoindol-2-yl]methyl}benzoicacid

The product from Example 33, Step 6 was deprotected using proceduressimilar to those described for Example 10, to give Example 33. ¹H-NMR(500 MHz, CDCl₃) δ 0.26-0.30 (1H, m, cyclopropane CHHCH₂), 0.36-0.40(1H, m, cyclopropane CHHCH₂), 0.50-0.59 (2H, m, cyclopropane CH₂CH₂),1.63 (6H, s, CH₃), 2.50 (1H, d, C—O—CHH), 3.29 (1H, d, C—O—CHH), 3.45(1H, d, CHHOH), 3.86 (1H, d, CHHOH), 5.01 (1H, d, N—CHH), 5.19 (1H, d,N—CHH), 7.08 (2H, d, H—Ar), 7.12 (1H, d, H—Ar), 7.16 (2H, d, H—Ar),7.25-7.26 (2H, m, H-4 and H—Ar), 7.73-7.77 (2H, m, H-5 and H—Ar), 8.04(1H, s, H-7). LCMS (ESI⁻) m/z=568.3[M−H]⁻.

Example 34:(3R)-2-{[4-chloro-2-(morpholine-4-sulfonyl)phenyl]methyl}-3-(4-chlorophenyl)-3-{[1-(hydroxymethyl)cyclopropyl]methoxy}-6-(2-hydroxypropan-2-yl)-2,3-dihydro-1H-isoindol-1-one

Example 34, Step 1, 4-Chloro-2-mercaptobenzonitrile

4-Chloro-2-fluorobenzonitrile (200 mg, 1.29 mmol) and Na₂S (110 mg, 1.41mmol) were added into a microwave vial, DMF (1 mL) was charged into themixture before stirring for 1 h at room temperature. 1 M NaOH solutionwas charged to pH 12 then washed by Et₂O (3×10 mL, acidified mixturewith 1 M HCl to pH 1-2 and extracted with Et₂O (3×10 mL), the combinedextracts were washed by water (30 mL) and brine (20 mL), dried by MgSO₄,concentrate in vacuo to give a yellow solid (156 mg, 72%). ¹H NMR (500MHz, CDCl₃) δ 4.14 (1H, s, SH), 7.21 (1H, d, J=8.4 Hz, H—Ar), 7.42 (1H,s, H—Ar), 7.52 (1H, d, J=8.3 Hz, H—Ar).

Example 34, Step 2, 4-Chloro-2-(morpholinosulfonyl)benzonitrile

To a stirring mixture of 4-chloro-2-mercaptobenzonitrile (50 mg, 0.30mmol), t-BuNCl (333 mg, 1.20 mmol) and H₂O (0.02 mL) in MeCN (3 mL) wasadded NCS (120 mg, 0.90 mmol) at 0° C., after 30 mins, morpholine (0.03mL, 0.30 mmol) was charged into reaction mixture before stirringovernight at room temperature, extracted with EtOAc (3×10 mL), thecombined organic extracts were washed with water (30 mL) and brine (20mL), dried by MgSO₄ and concentrated in vacuo. Chromatography (silica;EtOAc, petrol 20-50%) gave a white solid (59 mg, 70%). LCMS (ESI⁺)m/z=287.2 [M+H]⁺.

Example 34, Step 3, (4-Chloro-2-(morpholinosulfonyl)phenyl)methanamine

Prepared by the same method as described in Example 33, Step 1 (195 mg,0.68 mmol), THF (4 mL), 1 mol/L borane-THF complex (3.4 mL, 3.40 mmol)and 1 M HCl in MeOH (4 mL). Concentration in vacuo gave yellow oil (90mg, 46%). LCMS (ESI⁺) m/z=291.2 [M+H]⁺.

Example 34, Step 4,6-Acetyl-2-(4-chloro-2-(morpholinosulfonyl)benzyl)-3-(4-chlorophenyl)-3-hydroxyisoindolin-1-one

The title compound was prepared using procedures similar to thosedescribed for Preparation 9. LCMS (ESI⁻) m/z=573.3 [M−H]⁻.

Example 34, Step 5,6-Acetyl-2-(4-chloro-2-(morpholinosulfonyl)benzyl)-3-(4-chlorophenyl)-3-((1-(hydroxymethyl)cyclopropyl)methoxy)isoindolin-1-one

The title compound was prepared using procedures similar to thosedescribed in Preparation 22. LCMS (ESI⁺) m/z=681.4 [M+Na]⁺.

Example 34, Step 6,(3R)-2-{[4-chloro-2-(morpholine-4-sulfonyl)phenyl]methyl}-3-(4-chlorophenyl)-3-{[1-(hydroxymethyl)cyclopropyl]methoxy}-6-(2-hydroxypropan-2-yl)-2,3-dihydro-1H-isoindol-1-one

The title compound was prepared using procedures similar to thosedescribed for Example 1. ¹H-NMR (500 MHz, CDCl₃) δ 0.21-0.23 (1H, m,cyclopropane CHHCH₂), 0.30-0.32 (1H, m, cyclopropane CHHCH₂), 0.44-0.49(2H, m, cyclopropane CH₂CH₂), 1.65 (6H, s, CH₃), 1.85 (2H, bs, 2H), 2.66(1H, d, C—O—CHH), 2.96-3.01 (2H, m, H-morpholine), 3.07-3.11 (2H, m,H-morpholine), 3.18 (1H, d, C—O—CHH), 3.33 (1H, d, CHHOH), 3.64-3.71(4H, m, H-morpholine), 3.82 (1H, d, CHHOH), 4.92 (1H, d, N—CHH), 5.01(1H, d, N—CHH), 7.11 (2H, d, H—Ar), 7.18-7.24 (5H, m, H—Ar), 7.72 (1H,s, H—Ar), 7.79 (1H, d, H-5), 8.04 (1H, s, H-7). LCMS (ESI⁻) m/z=673.4[M−H]⁻.

Example 35:1-({[(1R)-2-[(4-chloro-2-methanesulfonylphenyl)methyl]-1-(4-chlorophenyl)-7-fluoro-5-(2-hydroxypropan-2-yl)-3-oxo-2,3-dihydro-1H-isoindol-1-yl]oxy}methyl)cyclopropane-1-carboxamide

Example 35, Step 1: Methyl 1-carbamoylcyclopropanecarboxylate

A solution of dimethyl cyclopropane-1,1-dicarboxylate (57.8 g, 0.365mol) in 7M ammonia in methanol was stirred at room temperature for 90 h,then evaporated under reduced pressure to afford the title compound as acolourless solid (52.2 g, 99%). ¹H NMR (400 MHz; DMSO-d₆): 7.82 (1H, s),7.35 (1H, s), 3.63 (3H, s), 1.34 (4H, s).

Example 35, Step 2: 1-(Hydroxymethyl)cyclopropanecarboxamide

Lithium aluminium hydride (27.2 g, 0.719 mol) was added portionwise over0.75 h. to a stirred suspension of methyl1-carbamoylcyclopropanecarboxylate (51.2 g, 0.358 mol) in THF (1.5 L) at0° C. under nitrogen. On complete addition the mixture was stirred at 0°C. for a further 1.25 h. prior to dropwise addition of water (27 mL),15% NaOH (27 mL) and water (82 mL) sequentially. The mixture was allowedto warm to room temperature, stirred for 0.5 h. and filtered throughcelite. The celite was washed with EtOAc and the combined filtrate andwashings evaporated to give the title compound as a colourless solid(33.4 g, 71%). ¹H NMR (400 MHz; DMSO-d₆): 7.10-6.85 (2H, m), 4.97 (1H,t), 3.48 (2H, d), 0.90-0.85 (2H, m), 0.61-0.58 (2H, m).

Example 35, Step 3: (4-Chloro-2-(methylsulfonyl)phenyl)methanamine

Hexamethylenetetramine (40.8 g, 0.291 mol) was added in one portion to astirred, room temperature solution of1-(bromomethyl)-4-chloro-2-(methylsulfonyl)benzene (75 g, 0.264 mol) inEtOAc (1 L). After 1.5 h. the mixture was chilled in ice and theprecipitate filtered, washed with cold EtOAc and air dried. Thismaterial was suspended in MeOH (375 mL), concentrated HCl (150 mL) addeddropwise over 0.33 h. and the mixture heated at 40° C. for 2 h. Themixture was cooled, concentrated under reduced pressure and the residuebasified with 5M NaOH, with cooling, and extracted with dichloromethane(3×500 mL). Combined extracts were dried (MgSO₄) and evaporated and theresidue chromatographed on silica gel eluting with 20-100% EtOAc inisohexane gradient followed by 0-10% MeOH containing 7N NH₃ in EtOAcgradient to afford the title compound as a pale brown solid (27.8 g,48%). 1H NMR (400 MHz, CDCl₃): 8.02 (1H, d), 7.58 (1H, dd), 7.51 (1H,d), 4.19 (2H, s), 3.23 (3H, s), 1.64 (2H, s).

Example 35, Step 4:(4-Chloro-2-(methylsulfonyl)phenyl)methanamine6-bromo-2-(4-chloro-2-(methylsulfonyl)benzyl)-3-(4-chlorophenyl)-4-fluoro-3-hydroxyisoindolin-1-one

HATU (45.6 g, 0.12 mol) was added to a stirred solution of5-bromo-2-(4-chlorobenzoyl)-3-fluorobenzoic acid (35.79 g, 0.1 mol) and(4-chloro-2-(methylsulfonyl)phenyl)methanamine (21.95 g, 0.1 mol) inanhydrous DMF (100 mL) at room temperature. The mixture was stirred atroom temperature for 18 h, at 60° C. for 18 h, then cooled andconcentrated under reduced pressure. The residual oil was poured intowater (1.5 L), extracted with dichloromethane (4×500 mL) and thecombined extracts washed with water (2×1 L), dried (MgSO₄) andevaporated and the residue chromatographed on silica gel eluting with20-100% EtOAc in isohexane gradient to give the title compound as a paleyellow solid (42.7 g, 76%). 1H NMR (400 MHz, CDCl₃): 7.88 (1H, d), 7.70(1H, d), 7.57 (1H, d), 7.49-7.45 (1H, m), 7.36-7.33 (1H, m), 7.25 (4H,s), 5.13 (1H, d), 4.73 (1H, d), 5.00-4.20 (1H, br s), 3.07 (3H, s).

Example 35, Step 5:1-(((5-Bromo-2-(4-chloro-2(methylsulfonyl)benzyl)-1-(4-chlorophenyl)-7-fluoro-3-oxoisoindolin-1yl)oxy)methyl)cyclopropanecarboxamide

The title compound was prepared using procedures similar to thosedescribed for Preparation 12. 1H NMR (400 MHz, CDCl₃): 7.99 (1H, d),7.93 (1H, dd), 7.75 (1H, d), 7.51-7.47 (1H, m), 7.30-7.19 (5H, m), 6.98(1H, s), 6.76 (1H, s), 4.99-4.88 (2H, m), 3.36-3.20 (5H, m), 1.05-0.90(2H, m), 0.63-0.53 (2H, m).

Example 35, Step 6:1-(((2-(4-Chloro-2-(methylsulfonyl)benzyl)-1-(4-chlorophenyl)-7-fluoro-3-oxo-5-(prop-1-en-2-yl)isoindolin-1-yl)oxy)methyl)cyclopropanecarboxamide

The title compound was prepared using procedures similar to thosedescribed for Preparation 13. H NMR (400 MHz; DMSO-d₆): 7.87 (1H, d),7.76 (1H, d), 7.70 (1H, dd), 7.50 (1H, dd), 7.30-7.20 (5H, m), 6.98 (1H,s), 6.70 (1H, s), 5.73 (1H, s), 5.33 (1H, s), 5.00-4.85 (2H, m),3.36-3.23 (5H, m), 2.20 (3H, s), 0.97-0.85 (2H, m), 0.65-0.45 (2H, m).

Example 35, Step 7:1-({[(1R)-2-[(4-chloro-2-methanesulfonylphenyl)methyl]-1-(4-chlorophenyl)-7-fluoro-5-(2-hydroxypropan-2-yl)-3-oxo-2,3-dihydro-1H-isoindol-1-yl]oxy}methyl)cyclopropane-1-carboxamide

The title compound was prepared using procedures similar to thosedescribed for Example 2. Chiral separation using supercritical fluidchromatography gave the title compound as the slower running isomer(0.245 g). 1H NMR (400 MHz, CDCl₃): 7.91-7.87 (2H, m), 7.53 (1H, d),7.37-7.30 (1H, m), 7.78-7.15 (5H, m), 6.53 (1H, s), 5.45 (1H, s),5.05-4.95 (2H, m), 3.36 (1H, d), 3.00 (3H, s), 2.96 (1H, d), 1.96 (1H,s), 1.65 (6H, s), 1.32-1.15 (2H, m), 0.60-0.30 (2H, m). MS(ES+) m/z633.3\635.3 [M+H]⁺.

Example 36:(3R)-2-[(4-chloro-2-methanesulfonylphenyl)methyl]-3-(4-chlorophenyl)-3-({1-[hydroxy(²H₂)methyl]cyclopropyl}(²H₂)methoxy)-6-(2-hydroxypropan-2-yl)-2,3-dihydro-1H-isoindol-1-oneExample 36 Step 1,6-Bromo-2-(4-chloro-2-(methylsulfonyl)benzyl)-3-(4-chlorophenyl)-3-hydroxyisoindolin-1-one

The title compound was prepared using procedures similar to thosedescribed for Preparation 9: LCMS (ESI⁻) m/z=538.0 [M−H]⁻.

Example 36 Step 2,6-Bromo-2-(4-chloro-2-(methylsulfonyl)benzyl)-3-(4-chlorophenyl)-3-((1-(deuteratedhydroxymethyl)cyclopropyl)deuteratedmethoxy)isoindolin-1-one

The title compound was prepared using procedures similar to thosedescribed for Preparation 22 but using1,1-bis(deuteratedhydroxymethyl)cyclopropane LCMS (ESI⁺) m/z=650.2[M+Na]⁺.

Example 36 Step 3:(3R)-2-[(4-chloro-2-methanesulfonylphenyl)methyl]-3-(4-chlorophenyl)-3-({1-[hydroxy(²H₂)methyl]cyclopropyl}(²H₂)methoxy)-6-(2-hydroxypropan-2-yl)-2,3-dihydro-1H-isoindol-1-one

Starting from Example 36, Step 2, the title compound was prepared usingprocedures similar to those described in Preparation 13 and Example 2.¹H-NMR (500 MHz, CDCl₃) δ 0.22-0.26 (1H, m, cyclopropane CHHCH₂),0.32-0.36 (1H, m, cyclopropane CHHCH₂), 0.45-0.51 (2H, m, cyclopropaneCH₂CH₂), 1.65 (6H, s, CH₃), 1.83 (2H, bs, 2H), 3.06 (3H, s, SO₂CH₃),5.02 (2H, s, N—CH₃), 7.13-7.20 (4H, m, H—Ar), 7.24-7.26 (2H, m, H—Ar),7.30 (1H, d, H—Ar), 7.79 (1H, d, H-5), 7.89 (1H, s, H—Ar), 8.02 (1H, s,H—Ar). LCMS (ESI⁺) m/z=608.4 [M+H]⁺

Example 37 and 38:(3R)-3-(4-Chlorophenyl)-2-[(4-chlorophenyl)methyl]-6-(2-hydroxypropan-2-yl)-3-(oxolan-3-yloxy)-2,3-dihydro-1H-isoindol-1-one

(*Both Isomers at the Position Shown)

The title compounds were prepared using procedures similar to thosedescribed in Preparations 10 and 13 and Example 2. The twodiastereoisomers were isolated by preparative chiral HPLC.

Example 37 (isomer 1): ¹H-NMR Spectrum: δ_(H) (500 MHz, CDCl3): 8.01(1H, d), 7.79 (1H, dd), 7.25-7.13 (9H, m), 4.52 (1H, d), 4.31 (1H, d),3.88-3.83 (2H, m), 3.59-3.55 (1H, m), 3.27-3.19 (2H, m), 1.79-1.74 (1H,m), 1.59 (6H, s), 1.53-1.46 (1H, m).

Example 38: (isomer 2): ¹H-NMR Spectrum: δ_(H) (500 MHz, CDCl₃): 8.01(1H, d), 7.79 (1H, dd), 7.21-7.13 (9H, m), 4.49 (1H, d), 4.43 (1H, d),3.88-3.82 (2H, m), 3.63-3.59 (1H, m), 3.49 (1H, dd), 3.14 (1H, dd),1.65-1.61 (2H, m), 1.59 (6H, s).

Example 39 and 40:(3R)-3-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-6-(2-hydroxypropan-2-yl)-3-[(oxolan-3-yl)methoxy]-2,3-dihydro-1H-isoindol-1-one

(*Both Isomers at the Position Shown)

Step 1; 3-(Hydroxymethyl)tetrahydrofuran

To a solution of tetrahydrofuran-3-carboxylic acid (0.247 mL, 2.58 mmol)in THF (13 mL) at 0° C. was added slowly lithium aluminium hydride (1.0M in THF, 5.2 mL, 5.16 mmol), stirred for 10 minutes then allowed toattain room temperature and stirred for a further 3 hours. The reactionmixture was cooled to 0° C. and diluted with diethyl ether (15 mL), thentreated sequentially with water (0.2 mL), NaOH (15% solution, 0.2 mL)and water (0.6 mL) and stirred for 30 minutes. The white suspension wasthen treated with sodium sulfate, stirred for a further 20 minutes,filtered over celite, washed with diethyl ether (2×20 mL) andconcentrated in vacuo to yield 224 mg (85%) of the title compound as acolourless oil which was carried forward to the next stage withoutfurther purification. ¹H-NMR Spectrum: δ_(H) (500 MHz, CDCl₃): 3.90-3.84(2H, m), 3.78-3.73 (1H, m), 3.66-3.63 (2H, m), 3.61-3.57 (1H, m),2.51-2.46 (1H, m), 2.08-2.01 (1H, m), 1.69-1.62 (1H, m)

Step 2:(3R)-3-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-6-(2-hydroxypropan-2-yl)-3-[(oxolan-3-yl)methoxy]-2,3-dihydro-1H-isoindol-1-one

(*Both Isomers at the Position Shown)

Starting from 3-(hydroxymethyl)tetrahydrofuran and Preparation 8, thetitle compounds were prepared using procedures similar to thosedescribed for Preparations 10 and 13 and Example 2. The twodiastereoisomers were isolated by preparative chiral HPLC.

Example 39 (*isomer 1): ¹H-NMR Spectrum: δ_(H) (500 MHz, (CD₃OD): 8.06(1H, d), 7.79 (1H, dd), 7.31-7.22 (8H, m), 7.16 (1H, d), 4.67 (1H, d),4.15 (1H, d), 3.77-3.75 (1H, m), 3.68-3.59 (2H, m), 3.49-3.47 (1H, m),2.79-2.77 (1H, m), 2.69-2.66 (1H, m), 2.10-2.02 (1H, m), 1.83-1.76 (1H,m), 1.59 (6H, s), 1.30-1.24 (1H, m).

Example 40 (*isomer 2): 1H-NMR Spectrum: δ_(H) (500 MHz, (CD₃OD): 7.94(1H, d), 7.68-7.66 (1H, m), 7.17-7.14 (4H, m), 7.07-7.04 (5H, m), 4.46(1H, d), 4.13 (1H, d), 3.59-3.55 (3H, m), 3.18-3.15 (1H, m), 2.68-2.60(2H, m), 2.12-2.04 (1H, m), 1.86-1.79 (1H, m), 1.47 (6H, s), 1.44-1.39(1H, m).

Examples 41 and 42:(3R)-2-[(4-chloro-2-methanesulfonylphenyl)methyl]-3-(4-chlorophenyl)-4-fluoro-6-[1-hydroxy-1-(oxan-4-yl)ethyl]-3-{[1-(hydroxymethyl)cyclopropyl]methoxy}-2,3-dihydro-1H-isoindol-1-one

(*Both Isomers at the Position Shown)

Step 1:6-Bromo-2-(4-chloro-2-(methylsulfonyl)benzyl)-3-(4-chlorophenyl)-4-fluoro-3-((1-(hydroxymethyl)cyclopropyl)methoxy)isoindolin-1-one

Thionyl chloride (3 mL, 42.2 mmol) was added dropwise to a solution of6-bromo-2-(4-chloro-2-(methylsulfonyl)benzyl)-3-(4-chlorophenyl)-4-fluoro-3-hydroxyisoindolin-1-one(Example 35, Step 4) (4.72 g, 8.44 mmol) in THF (50 mL) at 0° C. under anitrogen atmosphere. DMF (20 drops) were added and the orange solutionwas allowed to warm to rt over 1 d. The reaction mixture wasconcentrated in vacuo and dissolved in THF (40 mL).Cyclopropane-1,1-diyldimethanol (1.72 g, 16.9 mmol) was added followedby K₂CO₃ (2.33 g, 16.9 mmol) and the orange mixture was stirred at rtunder an atmosphere of nitrogen for 1 d. DCM and water were added andthe layers separated. The aqueous layer was extracted with DCM and thecombined organic layers were dried (phase separator) and concentrated invacuo. The residue was purified by Biotage (30-35% EtOAc in iso-hexanes)to give the title compound (3.33 g, 61%) as a pale yellow solid.

¹H NMR (400 MHz, DMSO) 8.01 (1H, d), 7.95 (1H, dd), 7.79 (1H, d), 7.56(1H, dd), 7.36 (2H, d), 7.30-7.26 (3H, m), 5.01-4.90 (2H, m), 4.45 (1H,t), 3.48-3.31 (2H, m), 3.29 (3H, s), 3.05-2.96 (2H, m), 0.42-0.40 (2H,m), 0.27 (1H, d), 0.19 (1H, dd).

Step 2:6-Acetyl-2-(4-chloro-2-(methylsulfonyl)benzyl)-3-(4-chlorophenyl)-4-fluoro-3-((1-(hydroxymethyl)cyclopropyl)methoxy)isoindolin-1-one

The title compound was prepared in a similar manner to that described inExample 21 Step 3, using6-bromo-2-(4-chloro-2-(methylsulfonyl)benzyl)-3-(4-chlorophenyl)-4-fluoro-3-((1-(hydroxymethyl)cyclopropyl)methoxy)isoindolin-1-one.

¹H NMR (400 MHz, DMSO) 8.30 (1H, d), 8.06 (1H, d), 7.80 (1H, d), 7.58(1H, dd), 7.38-7.28 (5H, m), 5.04-4.94 (2H, m), 3.48-3.30 (2H, m), 3.30(3H, s), 3.06-2.98 (2H, m), 2.75 (3H, s), 0.41 (2H, dd), 0.28-0.25 (1H,m), 0.16 (1H, d).

Step 3:(3R)-2-[(4-chloro-2-methanesulfonylphenyl)methyl]-3-(4-chlorophenyl)-4-fluoro-6-[1-hydroxy-1-(oxan-4-yl)ethyl]-3-{[1-(hydroxymethyl)cyclopropyl]methoxy}-2,3-dihydro-1H-isoindol-1-one

LaCl₃.2LiCl (0.6 M in THF, 1.93 mL, 1.16 mmol) was added to a solutionof6-acetyl-2-(4-chloro-2-(methylsulfonyl)benzyl)-3-(4-chlorophenyl)-4-fluoro-3-((1-(hydroxymethyl)cyclopropyl)methoxy)isoindolin-1-one(703 mg, 1.16 mmol) in THF (7 mL) under at atmosphere of nitrogen andthe yellow solution stirred at rt for 50 min and cooled to 0° C.(Tetrahydro-2H-pyran-4-yl)magnesium chloride (Novel Compound Solutions,0.5 M in 2-Me-THF, 23.2 mL, 11.6 mmol) was added slowly and the coolbath was removed. The red solution was allowed to warm to rt over 30 minand quenched with saturated aqueous NH₄Cl solution. DCM and water wereadded and the layers separated. The aqueous layer was extracted with DCMand the combined organic layers were washed with brine, dried (phaseseparator) and concentrated in vacuo. The residue was purified byBiotage (65-100% EtOAc in iso-hexanes) and submitted for chiralpurification by SFC.

Example 41, Diastereoisomer 1:

¹H NMR (400 MHz, CDCl3) 7.91 (1H, d), 7.76 (1H, d), 7.40-7.33 (2H, m),7.30-7.27 (2H, m), 7.24-7.17 (3H, m), 5.06-4.96 (2H, m), 4.07-3.93 (2H,m), 3.80 (1H, dd), 3.42-3.23 (4H, m), 3.04 (3H, s), 2.80 (1H, d), 2.00(1H, dd), 1.91-1.82 (1H, m), 1.79 (1H, s), 1.61 (3H, s), 1.53-1.40 (2H,m), 1.29-1.22 (2H, m), 0.51 (2H, s), 0.49-0.39 (1H, m), 0.22 (1H, d).MS(ES+) m/z 692 [M+H]⁺

Example 42, Diastereoisomer 2:

¹H NMR (400 MHz, CDCl3) 7.91 (1H, d), 7.72 (1H, s), 7.43 (1H, d), 7.36(1H, dd), 7.31-7.17 (5H, m), 5.07-4.96 (2H, m), 4.07-3.93 (2H, m), 3.81(1H, dd), 3.40-3.22 (4H, m), 3.03 (3H, s), 2.77 (1H, d), 2.01 (1H, s),1.86-1.80 (2H, m), 1.62 (3H, s), 1.52-1.39 (2H, m), 1.31-1.25 (2H, m),0.51 (2H, s), 0.49-0.40 (1H, m), 0.22 (1H, d). MS(ES+) m/z 692 [M+H]⁺

Examples 43 and 44:(3R)-2-[(4-chloro-2-methanesulfonylphenyl)methyl]-3-(4-chlorophenyl)-4-fluoro-6-[2-hydroxy-1-(piperazin-1-yl)propan-2-yl]-3-{[1-(hydroxymethyl)cyclopropyl]methoxy}-2,3-dihydro-1H-isoindol-1-one

(*Both Isomers at the Position Shown)

Step 1

The product from Example 41, Step 1 was purified by preparative chiralHPLC to provide(3R)-6-bromo-2-[(4-chloro-2-methanesulfonylphenyl)methyl]-3-(4-chlorophenyl)-4-fluoro-3-{[1-(hydroxymethyl)cyclopropyl]methoxy}-2,3-dihydro-1H-isoindol-1-oneas a single enantiomer. TBDMS protection (following a procedure similarto Preparation 11) gave(R)-6-acetyl-3-((1-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)methoxy)-2-(4-chloro-2-(methylsulfonyl)benzyl)-3-(4-chlorophenyl)-4-fluoroisoindolin-1-one.

Step 2:

60% Sodium Hydride dispersed in mineral oil (0.132 g; 3.44 mmol) wasadded portionwise over 10 minutes to a stirred solution of(R)-6-acetyl-3-((1-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)methoxy)-2-(4-chloro-2-(methylsulfonyl)benzyl)-3-(4-chlorophenyl)-4-fluoroisoindolin-1-one(1.56 g; 2.17 mmol) and trimethylsulfoxonium iodide (0.533 g; 2.42 mmol)in anhydrous DMSO (9 mL) and anhydrous THF (9 mL), at room temperature,under nitrogen. After 20 hours, water (400 mL) was added, the mixtureextracted with EtOAc (2×250 mL) and the combined organics dried (MgSO₄)and evaporated under reduced pressure. The residue was purified bychromatography on silica gel (100 g) eluting with 0-50% EtOAc inisohexane gradient to afford3-((1-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)methoxy)-2-(4-chloro-2-(methylsulfonyl)benzyl)-3-(4-chlorophenyl)-4-fluoro-6-(2-methyloxiran-2-yl)isoindolin-1-oneas a pale yellow foam (0.736 g, 46%). 1H NMR (400 MHz, CDCl₃): 7.90 (1H,d), 7.77 (1H, d), 7.40-7.27 (2H, m), 7.25-7.20 (2H, m), 7.22-7.10 (3H,m), 5.10-4.85 (2H, m), 3.85-3.70 (1H, m), 3.35-3.20 (2H, m), 3.10-3.00(1H, m), 2.97 (3H, s), 2.80-2.60 (2H, m), 1.55 (3H, s), 0.82 (9H, s),0.50-0.35 (2H, m), 0.25-0.05 (2H, m), 0.01 (6H, s).

Step 3 and 4:

Step 3 was performed by following procedures similar to those describedin Preparation 34 (but using piperazine instead of dimethylamine). Step4 was performed by following procedures similar to those described forExample 10. Chiral separation using supercritical fluid chromatographygave Example 43 (the faster running isomer) (74 mg, 30%). 1H NMR (400MHz, CDCl₃): 7.90 (1H, d), 7.77 (1H, d), 7.46 (1H, dd), 7.40-7.30 (1H,m), 7.30-7.10 (5H, m), 5.10-4.98 (2H, m), 3.82 (1H, d), 3.40-3.30 (1H,m), 3.30-3.20 (1H, m), 3.03 (3H, s), 2.85-2.65 (7H, m), 2.55-2.45 (2H,m), 2.38-2.25 (2H, m), 2.20-1.65 (3H, m), 1.51 (3H, s), 0.55-0.45 (2H,m), 0.45-0.35 (1H, m), 0.30-0.15 (1H, m). MS(ES+) m/z 706 [M+H]⁺.

Example 44 (the slower running isomer) (76 mg, 31%). 1H NMR (400 MHz,CDCl₃): 7.90 (1H, d), 7.75 (1H, d), 7.48 (1H, dd), 7.40-7.30 (1H, m),7.30-7.10 (5H, m), 5.10-4.90 (2H, m), 3.82 (1H, d), 3.40-3.30 (1H, m),3.30-3.20 (1H, m), 3.03 (3H, s), 2.85-2.65 (7H, m), 2.55-2.45 (2H, m),2.38-2.25 (2H, m), 2.20-1.65 (3H, m), 1.51 (3H, s), 0.55-0.45 (2H, m),0.45-0.35 (1H, m), 0.30-0.15 (1H, m). MS(ES+) m/z 706 [M+H]⁺.

Examples 45 and 46:(3R)-3-(4-Chlorophenyl)-2-[(1S)-1-(4-chlorophenyl)ethyl]-3-{[(3S,4R)-4-hydroxyoxolan-3-yl]oxy}-6-(2-hydroxypropan-2-yl)-2,3-dihydro-1H-isoindol-1-oneand(3R)-3-(4-chlorophenyl)-2-[(1S)-1-(4-chlorophenyl)ethyl]-3-{[(3R,4S)-4-hydroxyoxolan-3-yl]oxy}-6-(2-hydroxypropan-2-yl)-2,3-dihydro-1H-isoindol-1-one

Examples 45 and 46, Step 13-(4-Chlorophenyl)-2-[(1S)-1-(4-chlorophenyl)ethyl]-3-[(4-hydroxyoxolan-3-yl)oxy]-6-(prop-1-en-2-yl)-2,3-dihydro-1H-isoindol-1-one

The title compound (as a mixture for 4 isomers) was prepared using asimilar procedure as describe for Preparation 10, using1,4-anhydroerythritol and Preparation 13 The crude material was purifiedusing chromatography on silica (Pet:EtOAc 1:0 to 1:2) to give thedesired products as foamy colourless oil. The product (a mixture of 4isomers) was used directly in the next step.

Example 45 and Example 46, Step 2

Example 45 and Example 46 were prepared using similar procedure to thatdescribed for Example 2. The desired products were isolated was usingchromatography on silica (Pet:EtOAc 2:1 to 0:1).

Example 45 (isomer 1): R_(f)=0.25 (Pet:EtOAc/1:2). ¹H NMR (500 MHz,CDCl₃) δ (ppm) 1.61 (s, 3H, C(CH₃)₂), 1.62 (s, 3H, C(CH₃)₂), 1.85 (s,1H, C(CH₃)₂OH), 1.91 (d, 3H, J=7.3 Hz, NCHCH₃), 2.49 (d, 1H, J=3.6 Hz,CHOH), 3.27-3.37 (m, 1H, H-b), 3.67 (dd, 1H, J=10.4, 4.0 Hz, H-a), 3.83(dd, 1H, J=10.3, 1.2 Hz, H′-a), 3.87-4.01 (m, 3H, H-d, H′-d, H-c), 4.28(q, 1H, J=7.3 Hz, NCH), 6.94 (d, 2H, J=8.5 Hz, Ar—H), 6.97-7.09 (m, 6H,Ar—H); 7.20 (d, 1H, J=8.0 Hz, isoindolinone-H), 7.73 (d, 1H, J=7.9, 1.5Hz, isoindolinone-H), 7.98 (d, 1H, J=1.3 Hz, isoindolinone-H); MS(ES+)m/z 484.3 [M+H]⁺;

Example 46 (isomer 2): R_(f)=0.57 (Pet:EtOAc/1:2); ¹H NMR (500 MHz,CDCl₃) δ (ppm) 1.61 (s, 6H, C(CH₃)₂), 1.74 (d, 3H, J=7.2 Hz, NCHCH₃),1.82 (s, 1H, C(CH₃)₂OH), 2.06 (s, 1H, CHOH), 2.63-2.68 (m, 1H, H-b),2.71 (dd, 1H, J=8.5, 7.3 Hz, H-d), 3.28 (dd, 1H, J=8.5, 8.4 Hz, H′-d),3.42 (dd, 1H, J=10.3, 4.1 Hz, H-a), 3.44-3.49 (m, 1H, H-c), 3.53 (dd,1H, J=10.4, 1.5 Hz, H′-a), 4.19 (q, 1H, J=7.3 Hz, NCH), 6.97 (d, 1H,J=8.0 Hz, isoindolinone-H), 7.28 (d, 2H, J=8.4 Hz, Ar—H), 7.31-7.44 (m,4H, Ar—H), 7.57 (d, 2H, J=8.4 Hz, Ar—H), 7.68 (dd, 1H, J=7.9, 1.6 Hz,isoindolinone-H), 7.98 (d, 1H, J=1.3 Hz, isoindolinone-H); MS(ES+) m/z484.3 [M+H]⁺;

Example 47:(3R)-3-(4-Chlorophenyl)-2-[(4-chlorophenyl)methyl]-6-(2-hydroxypropan-2-yl)-3-methoxy-2,3-dihydro-1H-isoindol-1-one

Starting from Preparation 8 the title compound was prepared using(subsequently) processes similar to those described in Preparation 12;Example 21, step 3 and Example 1. ¹H-NMR Spectrum: (in CDCl₃) δ (ppm)1.61 (s, 6H, C(CH₃)₂), 2.12 (s, 1H, OH), 2.62 (s, 3H, OCH₃), 4.07 (d,1H, J=14.8 Hz, NCHH), 4.58 (d, 1H, J=14.8 Hz, NCHH), 7.06 (d, 1H, J=8.0Hz, Ar—H), 7.12-7.17 (m, 2H, Ar—H), 7.15-7.25 (m, 6H, Ar—H), 7.69 (dd,1H, J=8.0, 1.7 Hz, Ar—H), 8.00 (d, 1H, J=1.6 Hz, Ar—H. ms (M−H⁺)m/z=456.4.

Example 48:(3R)-3-(4-Chlorophenyl)-2-[(4-chlorophenyl)methyl]-3-({1-[hydroxy(²H₂)methyl]cyclopropyl}(²H₂)methoxy)-6-(2-hydroxypropan-2-yl)-2,3-dihydro-1H-isoindol-1-one

The title compound was prepared using procedures similar to thosedescribed for Example 1. ¹H NMR (500 MHz; CDCl₃) └_(H) 0.10-0.18 (2H, m,2×H-cyclopropyl), 0.38-0.44 (2H, m, 2×H-cyclopropyl), 1.52 (1H, br s,OH), 1.61 (3H, s, CH₃), 1.63 (3H, s, CH₃), 1.75 (1H, br s, OH), 4.18(1H, d, J=15.0 Hz, CH_(a)H_(b)Ph), 4.55 (1H, d, J=15.0 Hz,CH_(a)H_(b)Ph), 7.10 (1H, d, J=8.0 Hz, H-4), 7.12-7.23 (8H, m, H—Ar),7.72 (1H, dd, J=1.7 and 8.0 Hz, H-5), 7.99 (1H, d, J=1.7 Hz, H-7). LCMS(ES+) m/z 424.3, 426.3 [(M-c3 sidechain)+H]⁺

Example 49:(3R)-3-(4-Chlorophenyl)-2-[(4-chlorophenyl)methyl]-6-(2-hydroxypropan-2-yl)-3-(3-hydroxypropoxy)-2,3-dihydro-1H-isoindol-1-one

The title compound was prepared using procedures similar to thosedescribed for Example 1. 1H-NMR Spectrum: δ_(H) (500 MHz, CDCl3)1.40-1.55 (2H, m, CH₂CH₂CH₂OH), 1.60-1.64 (6H, m, 2×CH₃), 2.79-2.85 (1H,m, CH₂CH₂CH₂OH), 2.85-2.93 (1H, m, CH₂CH₂CH₂OH), 3.57 (2H, t, J=6.1 Hz,CH₂CH₂CH₂OH), 4.05 (1H, d, J=14.8 Hz, NC—H), 4.65 (1H, d, J=14.9 Hz,NC—H′), 7.08 (1H, d, J=7.9 Hz, ArH), 7.14-7.25 (8H, m, 8×ArH), 7.70 (1H,dd, J=1.7 and 7.9 Hz, ArH) and 7.99 (1H, d, J=1.2 Hz, 7-H); (ES+) m/z424.3 [M-O(CH-2)₃₀H]+

Example 50:(3R)-2-[(4-chloro-2-methanesulfonylphenyl)methyl]-3-(4-chlorophenyl)-4-fluoro-3-{[1-(hydroxymethyl)cyclopropyl]methoxy}-6-(2-hydroxypropan-2-yl)-2,3-dihydro-1H-isoindol-1-one

The title compound was prepared using procedures similar to thosedescribed for Example 36. 1H-NMR Spectrum: δ_(H) (500 MHz, CDCl3)0.17-0.25 (1H, m, Cy-Py-H), 0.38-0.42 (1H, m, Cy-Py-H), 0.46-0.53 (2H,m, Cy-Py-H2), 1.60-1.64 (6H, 2×s, 2×CH₃), 2.77 (1H, d, J=9.1 Hz, 2′-H),3.03 (3H, s, SO2CH3), 3.25 (1H, J=9.1 Hz, 2′-H′), 3.36 (1H, d, J=11.2Hz, 4′-H), 3.81 (1H, d, J=11.1 Hz, 4′-H′), 4.94-5.04 (2H, m, NC—H,NC—H′), 7.14-7.21 (3H, m, 3×ArH), 7.25-7.29 (2H, m, 2×ArH), 7.32 (1H,dd, J=2.3 and 8.4 Hz, ArH), 7.45 (1H, dd, J=1.3 and 10.8 Hz, ArH), 7.81(1H, d, J=1.4 Hz, ArH) and 7.89 (1H, d, J=2.3, 7-H). (ES+) m/z 520.3[M-C5H9O2]+

Example 51:(3R)-3-(4-Chlorophenyl)-2-[(4-chlorophenyl)methyl]-3-(2,2-difluoro-3-hydroxypropoxy)-6-(2-hydroxypropan-2-yl)-2,3-dihydro-1H-isoindol-1-one

Starting from Preparation 20 and difluoroprpoanediol, the title compoundwas prepared by following procedures similar to those described inPreparation 12 and Example 1. 1H-NMR Spectrum: δ_(H) (500 MHz, CDCl3)1.55 (3H, s, CH₃), 1.56 (3H, s, CH₃), 2.93-3.02 (2H, m, CH₂), 3.63-3.78(2H, m, CH₂), 4.19 (1H, d, J=15.0 Hz, NCHH′), 4.45 (1H, d, J=15.0 Hz,NCHH′), 7.04-7.11 (7H, m, 7×ArH), 7.13-7.15 (2H, m, 2×ArH), 7.67 (1H,dd, J=1.7 and 8.0 Hz, ArH), 7.94 (1H, d, J=1.7 Hz, ArH). m/z 536.4[M+H]+

Examples 52 and 53:(3R)-3-(4-Chlorophenyl)-2-[(4-chlorophenyl)methyl]-3-{[2-(hydroxymethyl)cyclobutyl]methoxy}-6-(2-hydroxypropan-2-yl)-2,3-dihydro-1H-isoindol-1-one

(Both Isomers as Shown)

Example 52 and 53, Step 1: (2-Hydroxymethyl-cyclobutyl)-methanol

A suspension of cyclobutane dicarboxylic acid (649 mg, 4.50 mmol) intetrahydrofuran (45 mL) was cooled to 0° C. and treated with lithiumaluminium hydride (1M in THF, 18.0 mL, 18.01 mmol) and stirred for 3hours. Once complete by TLC (SiO2; 30% MeOH in DCM) the reaction wasdiluted with diethyl ether (45 mL) and treated sequentially with water(0.68 mL), sodium hydroxide (15% aq., 0.68 mL) and water (2.1 mL) thenstirred for 30 minutes. Sodium sulphate was added and the solutionmixture stirred for a further 30 minutes. Once filtered the organiclayer was concentrated in vacuo to yield the title compound (305 mg,58%) as a colourless oil that was used without the need for furtherpurification.

Example 52 and 53, Step 2

Starting from (2-hydroxymethyl-cyclobutyl)-methanol, Example 52 and 53were made in a similar manner to Example 1. The two desired isomers wereisolated by preparative chiral HPLC.

Example 52 (isomer 1): δ_(H) (500 MHz, (CD₃OD): 8.05 (1H, d), 7.79 (1H,dd), 7.25-7.21 (4H, m), 7.19-7.14 (5H, m), 4.52 (1H, d), 4.33 (1H, d),3.54-3.49 (1H, m), 3.44-3.40 (1H, m), 3.06-3.03 (1H, m), 2.91-2.87 (1H,m), 2.53-2.49 (1H, m), 2.37-2.35 (1H, m), 2.04-1.96 (2H, m), 1.73-1.63(2H, m), 1.59 (6H, s).

Example 53 (isomer 2): δ_(H) (500 MHz, (CD₃OD): 8.06 (1H, d), 7.79 (1H,dd), 7.25-7.21 (4H, m), 7.19-7.14 (5H, m), 4.52 (1H, d), 4.33 (1H, d),3.54-3.49 (1H, m), 3.44-3.40 (1H, m), 3.06-3.03 (1H, m), 2.91-2.87 (1H,m), 2.53-2.48 (1H, m), 2.39-2.35 (1H, m), 2.04-1.96 (2H, m), 1.72-1.63(2H, m), 1.59 (6H, s).

Examples 54 and 55:(3R)-3-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-6-[2-hydroxy-1-oxo-1-(pyrrolidin-1-yl)propan-2-yl]-3-{[1-(hydroxymethyl)cyclopropyl]methoxy}-2,3-dihydro-1H-isoindol-1-one

(*Both Isomers at the Position Shown)

Example 54 and Example 55, Step 1:(R)-3-((1-(((tert-Butyldimethylsilyl)oxy)methyl)cyclopropyl)methoxy)-2-(4-chlorobenzyl)-3-(4-chlorophenyl)-6-(prop-1-en-2-yl)isoindolin-1-one

TBSCl (2.62 g, 17.4 mmol, 1.5 eq.), imidazole (1.19 g, 1.5 eq.) and2-(4-chlorobenzyl)-3-(4-chlorophenyl)-3-((1-(hydroxymethyl) cyclopropyl)methoxy)-6-(prop-1-en-2-yl)isoindolin-1-one (R-isomer) (5.9 g, 11.6mmol, 1 eq,) were dissolved in THF (100 mL) and heated to 50° C. for 6h. Allowed to cool to r.t., and partitioned between EtOAc (2×70 mL) andH₂O (70 mL). Organic extracts were combined, dried over MgSO₄, andsolvent removed in vacuo. The residue was purified by MPLC (1-5%EtOAc/petrol) to give a clear oil (6.045 g, 84%); ¹H NMR (500 MHz;CDCl₃) 5-0.02 (3H, s, CH₃Si), 0.00 (3H, s, CH₃Si), 0.07-0.12 (2H, m,cPr), 0.33-0.38 (2H, m, cPr), 0.83 (9H, s, tBu), 1.27 (3H, s, Me),2.16-2.19 (2H, brs), 2.62 (1H, d, CH_(a)H_(b)O), 2.89 (1H, d,CH_(a)H_(b)O), 3.36 (1H, d, CH_(a)H_(b)O), 3.65 (1H, d, CH_(a)H_(b)O),4.32 (1H, d, CH_(a)H_(b)N), 4.39 (1H, d, CH_(a)H_(b)N)), 5.18 (1H, m,H-alkene), 5.44 (1H, m, H-alkene), 7.01-7.22 (9H, m, H—Ar), 7.58 (1H,dd, H-5), 7.96 (1H, d, H-7).

Example 54 and Example 55, Step 2(3R)-3-((1-(((tert-Butyldimethylsilyl)oxy)methyl)cyclopropyl)methoxy)-2-(4-chlorobenzyl)-3-(4-chlorophenyl)-6-(1,2-dihydroxypropan-2-yl)isoindolin-1-one

The title compound was prepared using procedures similar to thosedescribed for Example 27, giving product as a mixture of 2diastereoisomers). ¹H NMR (500 MHz; CDCl₃) δ −0.02 (3H, s, CH₃Si), 0.00(3H, s, CH₃Si), 0.07-0.13 (2H, m, cPr), 0.33-0.39 (2H, m, cPr), 0.83(9H, s, tBu), 1.56 (3H, s, Me), 1.82 (1H, br s, OH), 2.60 (1H, d,CH_(a)H_(b)O), 2.64 (1H, br s, OH), 2.88 (1H, d, CH_(a)H_(b)O), 3.36(1H, d, CH_(a)H_(b)O), 3.62-3.74 (2H, m, CH_(a)H_(b)O andCH_(a)H_(b)OH), 3.81 (1H, d, CH_(a)H_(b)OH), 4.31 (1H, d, CH_(a)H_(b)N),4.40 (1H, d, CH_(a)H_(b)N)), 7.03-7.13 (5H, m, H—Ar), 7.13-7.20 (4H, m,H—Ar), 7.67 (1H, dd, H-5), 7.94 (1H, d, J=1.5 Hz, H-7); MS ES+ 440.3,442.3 [M-sidechain]⁺.

Example 54 and Example 55, Step 32-((R)-1-((1-(((tert-Butyldimethylsilyl)oxy)methyl)cyclopropyl)methoxy)-2-(4-chlorobenzyl)-1-(4-chlorophenyl)-3-oxoisoindolin-5-yl)-2-hydroxypropanoicacid

TEMPO (161 mg, 1.03 mmol, 0.25 eq.), NaClO₂ (744 mg, 8.22 mmol, 2 eq.)and NaOCl (30 μL, 0.08 mmol, 0.02 eq.) were added to

(3R)-3-((1-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)methoxy)-2-(4-chlorobenzyl)-3-(4-chlorophenyl)-6-(1,2-dihydroxypropan-2-yl)isoindolin-1-one(2.7 g, 4.11 mmol, 1 eq.) in a mixture of MeCN (20 mL) and sodiumphosphate buffer (pH 6.5, 16 mL), and the mixture was stirred at r.t.for 5 days. Water was added, and the pH adjusted to pH 8 with NaOH (1 Maq.). Na₂SO₃ (aq) was added, and the pH adjusted to pH 2 with HCl (1 Maq). The mixture was extracted with EtOAc (2×50 mL), dried over MgSO₄,and the solvent was removed in vacuo. Purification by MPLC on silicawith a gradient from 0-10% MeOH/DCM gave a white foam (2.27 g, 83%, ca.3:1 mixture of diastereoisomers); Major diastereoisomer: ¹H NMR (500MHz; CDCl₃) δ 0.00 (3H, s, CH₃Si), 0.02 (3H, s, CH₃Si), 0.10-0.17 (2H,m, cPr), 0.35-0.42 (2H, m, cPr), 0.85 (9H, s, tBu), 1.94 (3H, s, Me),2.65 (1H, d, CH_(a)H_(b)O), 2.90 (1H, d, CH_(a)H_(b)O), 3.39 (1H, d,CH_(a)H_(b)O), 3.65 (1H, m, CH_(a)H_(b)O), 3.81 (1H, d, CH_(a)H_(b)OH),4.35 (1H, d, CH_(a)H_(b)N), 4.41 (1H, d, CH_(a)H_(b)N)), 7.00-7.20 (9H,m, H—Ar), 7.96 (1H, dd, H-5), 8.29 (1H, d, H-7); MS ES− 668.3, 670.3[M−H]⁻.

Example 54 and Example 55, Step 4

The title compound was prepared from2-((R)-1-((1-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)methoxy)-2-(4-chlorobenzyl)-1-(4-chlorophenyl)-3-oxoisoindolin-5-yl)-2-hydroxypropanoicacid, using PyBrop and pyrrolidine. Deprotection, using similarprocedures to those described for Example 10, followed by preparativeHPLC gave the two isomers.

Example 54 (*isomer 1). ¹H-NMR Spectrum: (500 MHz, CDCl₃) δ 0.12-0.18(2H, m, cyclopropane CH₂CH₂), 0.40-0.44 (2H, m, cyclopropane CH₂CH₂),1.55-1.59 (2H, m, H-pyrrolidine), 1.72-1.77 (3H, m, H-pyrrolidine andOH), 1.85 (3H, s, CH₃), 2.56-2.61 (1H, m, H-pyrrolidine), 2.72 (1H, d,J=9.4 Hz, C—O—CHH), 2.76 (1H, d, J=9.4 Hz, C—O—CHH), 3.09-3.14 (1H, m,H-pyrrolidine), 3.39 (1H, d, J=11.4 Hz, CHHOH), 3.47 (1H, d, J=11.4 Hz,CHHOH), 3.51-3.56 (2H, m, H-pyrrolidine), 4.24 (1H, d, J=14.9 Hz,N—CHH), 4.51 (1H, d, J=14.9 Hz, N—CHH), 5.44 (1H, s, OH), 7.11-7.21 (9H,m, H—Ar), 7.51 (1H, d, J=8.0 Hz, H-5), 8.0 (1H, s, H-7). MS (ESI⁺)m/z=507.4 [M+H]⁺

Example 55 (*isomer 2): ¹H-NMR Spectrum: (500 MHz, CDCl₃) δ 0.09-0.13(2H, m, cyclopropane CH₂CH₂), 0.38-0.43 (2H, m, cyclopropane CH₂CH₂),1.51-1.59 (2H, m, H-pyrrolidine), 1.70-1.78 (3H, m, H-pyrrolidine andOH), 1.85 (3H, s, CH₃), 2.59-2.66 (2H, m, H-pyrrolidine and C—O—CHH),2.74 (1H, d, J=9.3 Hz, C—O—CHH), 3.05-3.10 (1H, m, H-pyrrolidine), 3.33(1H, d, J=11.3 Hz, CHHOH), 3.48 (1H, d, J=11.3 Hz, CHHOH), 3.55-3.58(2H, m, H-pyrrolidine), 4.17 (1H, d, J=14.8 Hz, N—CHH), 4.54 (1H, d,J=14.8 Hz, N—CHH), 5.38 (1H, s, OH), 7.11-7.22 (9H, m, H—Ar), 7.53 (1H,d, J=8.1 Hz, H-5), 8.0 (1H, s, H-7). MS (ESI⁺) m/z=507.4 [M+H]⁺

Examples 56 and 57:2-[(1R)-1-(4-Chlorophenyl)-2-[(4-chlorophenyl)methyl]-1-{[1-(hydroxymethyl)cyclopropyl]methoxy}-3-oxo-2,3-dihydro-1H-isoindol-5-yl]-2-hydroxy-N,N-dimethylpropanamidedimethylpropanamide (*Both Isomers at the Position Highlighted) Example56 and 57, Step 12-((R)-1-((1-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)methoxy)-2-(4-chlorobenzyl)-1-(4-chlorophenyl)-3-oxoisoindolin-5-yl)-2-hydroxy-N,N-dimethylpropanamide

To a solution of2-((R)-1-((1-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)methoxy)-2-(4-chlorobenzyl)-1-(4-chlorophenyl)-3-oxoisoindolin-5-yl)-2-hydroxypropanoicacid (Example 54 and Example 55, step 3) (400 mg, 0.60 mmol), PyBroP(420 mg, 0.90 mmol) and pyridine (0.05 mL, 0.60 mmol) in MeCN (4 mL) wasadded dimethylamine solution (2M in MeCN, 0.75 mL, 1.5 mmol) beforestirring at room temperature overnight. The reaction was extracted withEtOAc (3×10 mL), the combined organic extracts were washed with water(30 mL) and brine (20 mL), dried by MgSO₄ and concentrated in vacuo.Chromatography (silica; EtOAc, petrol 20-90%) gave a white solid (250mg, 71%). LCMS (ESI⁺) m/z=719.5 [M+Na]⁺.

Example 56 and 57, Step 22-((R)-2-(4-Chlorobenzyl)-1-(4-chlorophenyl)-1-((1-(hydroxymethyl)cyclopropyl)methoxy)-3-oxoisoindolin-5-yl)-2-hydroxy-N,N-dimethylpropanamide(*Both Isomers at the Position Highlighted)

The title compound was prepared using procedures similar to thosedescribed for Example 10. Purification by chiral HPLC gave the titlecompound:

¹H-NMR (500 MHz, CDCl₃) δ 0.11-0.15 (2H, m, cyclopropane CH₂CH₂),0.39-0.43 (2H, m, cyclopropane CH₂CH₂), 1.63 (1H, brs, OH), 1.86 (3H, s,CH₃), 2.59-2.64 (4H, m, C—O—CHH and N—CH₃), 2.80 (1H, d, C—O—CHH), 3.02(3H, brs, N—CH₃), 3.34 (1H, d, CHHOH), 3.50 (1H, d, CHHOH), 4.18 (1H, d,N—CHH), 4.54 (1H, d, N—CHH), 5.39 (1H, s, OH), 7.11-7.18 (7H, m, H—Ar),7.21 (2H, d, H—Ar), 7.50 (1H, d, H-5), 8.0 (1H, s, H-7). LCMS (ESI⁻)m/z=627.4 [M+Formate]⁻.

Example 56 (*isomer 1): ¹H-NMR Spectrum: (500 MHz, CDCl₃) δ 0.12-0.18(2H, m, cyclopropane CH₂CH₂), 0.40-0.44 (2H, m, cyclopropane CH₂CH₂),1.59 (1H, brs, OH), 1.87 (3H, s, CH₃), 2.59 (3H, brs, N—CH₃), 2.70 (1H,d, J=9.4 Hz, C—O—CHH), 2.79 (1H, d, J=9.4 Hz, C—O—CHH), 3.00 (3H, brs,N—CH₃), 3.38 (1H, d, J=11.4 Hz, CHHOH), 3.48 (1H, d, J=11.4 Hz, CHHOH),4.24 (1H, d, J=14.8 Hz, N—CHH), 4.51 (1H, d, J=14.8 Hz, N—CHH), 5.44(1H, s, OH), 7.11-7.17 (7H, m, H—Ar), 7.20 (2H, d, J=8.9 Hz, H—Ar), 7.47(1H, d, J=8.0 Hz, H-5), 8.0 (1H, s, H-7). MS (ESI⁺) m/z=481.3 [M+H]⁺

Example 57 (*isomer 2): ¹H-NMR Spectrum: (500 MHz, CDCl₃) δ 0.11-0.15(2H, m, cyclopropane CH₂CH₂), 0.39-0.43 (2H, m, cyclopropane CH₂CH₂),1.63 (1H, brs, OH), 1.86 (3H, s, CH₃), 2.59-2.64 (4H, m, C—O—CHH andN—CH₃), 2.80 (1H, d, J=9.5 Hz, C—O—CHH), 3.02 (3H, brs, N—CH₃), 3.34(1H, d, J=11.3 Hz, CHHOH), 3.50 (1H, d, J=11.3 Hz, CHHOH), 4.18 (1H, d,J=14.8 Hz, N—CHH), 4.54 (1H, d, J=14.8 Hz, N—CHH), 5.39 (1H, s, OH),7.11-7.18 (7H, m, H—Ar), 7.21 (2H, d, J=8.9 Hz, H—Ar), 7.50 (1H, d,J=8.0 Hz, H-5), 8.0 (1H, s, H-7). MS (ESI′) m/z=481.3 [M+H]⁺

Examples 58 and 59:2-[(1R)-1-(4-Chlorophenyl)-2-[(4-chlorophenyl)methyl]-1-{[1-(hydroxymethyl)cyclopropyl]methoxy}-3-oxo-2,3-dihydro-1H-isoindol-5-yl]-2-hydroxy-N-methylpropanamide

(*Both Isomers at the Position Highlighted)

The title compound was prepared from2-((R)-1-((1-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)methoxy)-2-(4-chlorobenzyl)-1-(4-chlorophenyl)-3-oxoisoindolin-5-yl)-2-hydroxypropanoicacid, using PyBrop and methylamine. Deprotection, using similarprocedures to those described for Example 10, followed by preparativeHPLC gave the two isomers.

Example 58 (*isomer 1): ¹H-NMR: (500 MHz, CDCl₃) δ 0.13-0.19 (2H, m),0.39-0.44 (2H, m), 1.67 (1H, brs), 1.84 (3H, s), 2.66 (1H, d), 2.79 (3H,d), 2.83 (1H, d), 3.36 (1H, d), 3.48 (1H, d), 4.05 (1H, s), 4.21 (1H,d), 4.50 (1H, d), 6.88 (1H, q), 7.08-7.18 (9H, m), 7.82 (1H, d), 8.23(1H, s). LCMS (ESI⁻) m/z=567.3 [M−H]⁻

Example 59 (*isomer 2): ¹H-NMR: (500 MHz, CDCl₃) δ 0.12-0.18 (2H, m),0.38-0.43 (2H, m), 1.85 (3H, s), 2.63 (1H, d), 2.79 (3H, d), 2.85 (1H,d), 3.34 (1H, d, J=11.4 Hz, CHHOH), 3.50 (1H, d, J=11.4 Hz, CHHOH), 4.19(1H, d), 4.52 (1H, d), 6.90 (1H, q), 7.09-7.20 (9H, m), 7.81 (1H, d),8.23 (1H). LCMS (ESI⁻) m/z=567.3 [M−H]⁻

Examples 60:(3R)-2-{[4-chloro-2-(methylsulfanyl)phenyl]methyl}-3-(4-chlorophenyl)-4-fluoro-3-{[1-(hydroxymethyl)cyclopropyl]methoxy}-6-(2-hydroxypropan-2-yl)-2,3-dihydro-1H-isoindol-1-one

Starting from 5-bromo-2-(4-chlorobenzoyl)-3-fluorobenzoic acid andPreparation 43 (4-chloro-2-(methylthio)phenyl)methanamine), the titlecompound was prepared by following procedures similar to those describedin Preparation 9, Preparation 10, Example 21, Step 3 and Example 1; in asequential manner.

¹H NMR (500 MHz, CDCl₃) δ7.81 (1H, s, H-7), 7.39 (1H, d5), 7.23 (2H, d,7.16-7.19 (3H, m), 7.01 (1H, s), 6.96 (1H, d), 4.68 (1H, d), 4.43 (1H,d), 3.49 (1H, q), 3.41 (1H, q), 2.95 (1H, d), 2.89 (1H, d), 2.38 (3H,s), 1.90 (1H, s), 1.71 (1H, t), 1.61 (6H, d), 0.41-0.48 (2H, m),0.28-0.31 (1H, m), 0.14-0.17 (1H, m). LCMS (ESI⁻) m/z=634.3 [M+Formate]⁻

Examples 61 and 62:(3R)-2-[(4-Chloro-2-methanesulfinylphenyl)methyl]-3-(4-chlorophenyl)-4-fluoro-3-{[1-(hydroxymethyl)cyclopropyl]methoxy}-6-(2-hydroxypropan-2-yl)-2,3-dihydro-1H-isoindol-1-one

(*Both Isomers at Position Highlighted)

To a solution of(3R)-2-{[4-chloro-2-(methylsulfanyl)phenyl]methyl}-3-(4-chlorophenyl)-4-fluoro-3-{[1-(hydroxymethyl)cyclopropyl]methoxy}-6-(2-hydroxypropan-2-yl)-2,3-dihydro-1H-isoindol-1-one(Example 60) (140 mg, 0.24 mmol) in MeOH (3 mL) was added sodiumperiodate (56 mg, 0.26 mmol) in portions over 3 mins at 0° C. Themixture was stirred overnight, H₂O was added, and extracted with EtOAc.The combined organic extracts were washed with brine, dried (MgSO₄) andconcentrated in vacuo. Chromatography (SP4, silica; MeOH/EtOAc 0-30%)gave the products as white solids (70 mg, 48% and 70 mg, 48%).

Example 61: *fast running isomer: ¹H NMR (500 MHz, CDCl₃) δ 7.85 (1H,d′), 7.81 (1H, d), 7.48 (1H, d), 7.40 (1H, dd), 7.30-7.34 (3H, m),7.25-7.26 (2H, m), 4.71 (1H, d), 4.28 (1H, d), 3.62 (1H, d), 3.33 (1H,d), 2.82 (1H, d), 2.72 (1H, d), 2.62 (3H, s, CH₃), 2.27 (1H, br s), 1.99(1H, s), 1.62 (3H, s), 1.61 (3H, s), 0.39-0.44 (2H, m), 0.19-0.21 (1H,m), 0.01-0.03 (1H, m). LCMS (ESI⁺) m/z=682.3 [M+Na]⁺;

Example 62: *slow running isomer: ¹H NMR (500 MHz, CDCl₃) δ 7.82 (1H,d), 7.78 (1H, d), 7.42 (1H, dd), 7.24 (1H, dd), 7.15-7.19 (4H, m), 7.13(1H, d), 4.60 (1H, d), 4.46 (1H, d), 3.59 (1H, dd, J=6.1 and 11.5 Hz,CHHOH), 3.49 (1H, dd, J=6.1 and 11.5 Hz, CHHOH), 3.04 (1H, d), 2.91 (1H,d), 1.90 (1H, s), 2.72 (3H, s), 1.67 (1H, t), 1.63 (3H, s), 1.62 (3H,s), 0.41-0.49 (2H, m), 0.30-0.33 (1H, m), 0.05-0.09 (1H, m). LCMS (ESI⁺)m/z=628.3 [M+Na]⁺

Examples 63 and 64:(3R)-2-[(4-Chloro-2-methanesulfonylphenyl)methyl]-3-(4-chlorophenyl)-4-fluoro-6-(2-hydroxy-1-methoxypropan-2-yl)-3-{[1-(hydroxymethyl)cyclopropyl]methoxy}-2,3-dihydro-1H-isoindol-1-one

(*Both Isomers at the Position Highlighted)

The title compounds were prepared using methods similar to thosedescribed in Example 43; but using sodium methoxide instead ofpiperazine.

Example 63 (the faster running isomer) (31 mg, 14%). 1H NMR (400 MHz,DMSO-d6): 7.85 (1H, d), 7.77 (1H, d), 7.58-7.50 (2H, m), 7.34-7.23 (5H,m), 5.49 (1H, s), 5.02-4.66 (2H, m), 4.39 (1H, t), 3.53-3.44 (2H, m),3.28 (3H, s), 3.24 (3H, s), 3.02 (1H, d), 2.89 (1H, d), 1.47 (3H, s),0.41-0.32 (2H, m), 0.26-0.17 (1H, m), 0.06 (1H, d). MS(ES+) m/z 652[M+H]⁺.

Example 64 (the slower running isomer) (11 mg, 5%). 1H NMR (400 MHz,DMSO-d6): 7.85 (1H, d), 7.77 (1H, d), 7.57-7.50 (2H, m), 7.33-7.22 (5H,m), 5.49 (1H, s), 5.01-4.81 (2H, m), 4.39 (1H, t), 3.54-3.44 (2H, m),3.28 (3H, s), 3.24 (3H, s), 3.02 (1H, d), 2.90 (1H, d), 1.47 (3H, s),0.37 (2H, d), 0.27-0.18 (1H, m), 0.11-0.03 (1H, m). MS(ES+) m/z 652[M+H]⁺.

Examples 65 and 66:(3R)-2-[(4-Chloro-2-methanesulfonylphenyl)methyl]-3-(4-chlorophenyl)-6-(1,2-dihydroxypropan-2-yl)-4-fluoro-3-{[1-(hydroxymethyl)cyclopropyl]methoxy}-2,3-dihydro-1H-isoindol-1-one

(*Both Isomers at the Position Shown)

The title compounds were prepared using methods similar to thosedescribed in Example 41, Step 1 and Example 27; in a sequential manner.

Example 65 (faster running, major isomer, 174 mg, 26%): 1H NMR (400 MHz,DMSO-d6): 7.84 (1H, d), 7.77 (1H, d), 7.58-7.50 (2H, m), 7.32-7.21 (5H,m), 5.30 (1H, s), 4.98-4.80 (3H, m), 4.39 (1H, t), 3.57-3.40 (3H, m),3.25 (3H, s), 3.03 (1H, d), 2.90 (1H, d), 1.46 (3H, s), 0.37 (2H, s),0.27-0.18 (1H, m), 0.07 (1H, d). MS(ES+) m/z 638 [M+H]⁺.

Example 66 (slower running, minor isomer, 74 mg, 11%): 1H NMR (400 MHz,DMSO-d6): 7.85 (1H, dd), 7.77 (1H, d), 7.57-7.48 (2H, m), 7.32-7.23 (5H,m), 5.30 (1H, s), 4.99-4.79 (3H, m), 4.39 (1H, t), 3.57-3.39 (3H, m),3.25 (3H, s), 3.02 (1H, d), 2.94-2.87 (1H, m), 1.46 (3H, s), 0.37 (2H,s), 0.28-0.17 (1H, m), 0.08 (1H, d). MS(ES+) m/z 638 [M+H]⁺.

Examples 67 and 68:(3R)-2-[(4-Chloro-2-methanesulfonylphenyl)methyl]-3-(4-chlorophenyl)-4-fluoro-6-[2-hydroxy-1-(4-methylpiperazin-1-yl)propan-2-yl]-3-[(3R)-oxolan-3-yloxy]-2,3-dihydro-1H-isoindol-1-one(*Both Isomers at the Position Shown)

Starting from Preparation 44, the title compounds were prepared usingmethods similar to those described in Example 43, steps 2 and 3 (butusing N-methyl-piperazine instead of piperazine).

Example 67 (faster running isomer, 132 mg, 28%): 1H NMR (400 MHz,DMSO-d6): 7.92 (1H, d), 7.80 (1H, d), 7.60-7.49 (2H, m), 7.36-7.19 (5H,m), 5.26 (1H, s), 5.09-4.67 (2H, m), 4.02-3.94 (1H, m), 3.78 (1H, q),3.57-3.48 (1H, m), 3.27-3.15 (4H, m), 2.61 (1H, d), 2.34 (4H, s), 2.16(4H, s), 2.08 (3H, s), 1.74-1.62 (1H, m), 1.59-1.38 (4H, m). MS(ES+) m/z706 [M+H]⁺.

Example 68 (slower running isomer, 131 mg, 28%): 1H NMR (400 MHz,DMSO-d6): 7.85 (1H, d), 7.78 (1H, d), 7.62-7.51 (2H, m), 7.32-7.20 (5H,m), 5.23 (1H, s), 4.92 (2H, s), 3.99-3.92 (1H, m), 3.78 (1H, q),3.58-3.49 (1H, m), 3.43-3.36 (1H, m), 3.24 (3H, s), 2.59 (1H, d), 2.35(5H, d), 2.16 (4H, s), 2.08 (3H, s), 1.74-1.63 (1H, m), 1.57-1.40 (4H,m). MS(ES+) m/z 706 [M+H]⁺.

Examples 69 and 70:(3R)-2-[(4-Chloro-2-methanesulfonylphenyl)methyl]-3-(4-chlorophenyl)-4-fluoro-6-[2-hydroxy-1-(4-methylpiperazin-1-yl)propan-2-yl]-3-[(3S)-oxolan-3-yloxy]-2,3-dihydro-1H-isoindol-1-one(*Both Isomers at the Position Shown)

The title compounds were prepared using procedures similar to thosedescribed in Examples 67 and 68, but using (3S)-hydroxy-tetrahydrofuran.

Example 69 (faster running isomer, 96 mg, 39%): 1H NMR (400 MHz,DMSO-d6): 7.92 (1H, d), 7.78 (1H, d), 7.59-7.50 (2H, m), 7.34-7.19 (5H,m), 5.27 (1H, s), 5.06-4.71 (2H, m), 4.01-3.93 (1H, m), 3.75 (1H, q),3.60-3.51 (1H, m), 3.45-3.40 (1H, m), 3.24 (3H, s), 3.15 (1H, dd), 2.61(1H, d), 2.41-2.26 (5H, m), 2.16 (4H, s), 2.07 (3H, s), 1.81-1.64 (1H,m), 1.59 (1H, d), 1.50 (3H, s). MS(ES+) m/z 706 [M+H]⁺.

Example 70 (slower running isomer, 97 mg, 39%): 1H NMR (400 MHz,DMSO-d6): 7.84 (1H, d), 7.77 (1H, d), 7.63-7.50 (2H, m), 7.30-7.19 (5H,m), 5.23 (1H, s), 4.98 (2H, s), 3.99-3.92 (1H, m), 3.77 (1H, q),3.62-3.54 (1H, m), 3.46-3.40 (1H, m), 3.25 (3H, s), 3.17 (1H, dd), 2.59(1H, d), 2.34 (5H, s), 2.16 (4H, s), 2.08 (3H, s), 1.86-1.73 (1H, m),1.73-1.61 (1H, m), 1.53 (3H, s). MS(ES+) m/z 706 [M+H]⁺.

Example 71:(3S)-3-(4-Chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-(2-hydroxypropan-2-yl)-3-oxo-1-[(3S)-oxolan-3-yloxy]-2,3-dihydro-1H-isoindol-2-yl]propanoicacid

Step 1:(3S)-3-[(1R)-5-Acetyl-1-(4-chlorophenyl)-7-fluoro-3-oxo-1-[(3S)-oxolan-3-yloxy]-2,3-dihydro-1H-isoindol-2-yl]-3-(4-chlorophenyl)propanoicacid

The title compound was prepared from ethyl(3S)-3-[(1R)-5-acetyl-1-(4-chlorophenyl)-7-fluoro-3-oxo-1-[(3S)-oxolan-3-yloxy]-2,3-dihydro-1H-isoindol-2-yl]-3-(4-chlorophenyl)propanoate(Preparation 45) in a similar manner as described in Preparation 40.MS(ES+) m/z 570 [M−H]⁻

Step 2:(3S)-3-(4-Chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-(2-hydroxypropan-2-yl)-3-oxo-1-[(3S)-oxolan-3-yloxy]-2,3-dihydro-1H-isoindol-2-yl]propanoicacid

Using the product from Step 1, the title compound was prepared in asimilar fashion to Example 1.

1H NMR (400 MHz, DMSO-d6): 12.42 (1H, s), 7.79 (1H, s), 7.51 (1H, d),7.10 (4H, dd), 6.99 (4H, d), 5.36 (1H, s), 4.62 (1H, dd), 4.21-4.13 (1H,m), 3.92 (1H, q), 3.77-3.63 (2H, m), 3.50 (1H, d), 3.23 (1H, dd), 3.12(1H, dd), 2.25-2.09 (1H, m), 2.09-1.94 (1H, m), 1.47 (6H, s); MS(ES+)m/z 570 [M−H]⁻

Example 72:1-({[(1R)-2-{[4-Chloro-2-(hydroxymethyl)phenyl]methyl}-1-(4-chlorophenyl)-7-fluoro-5-(2-hydroxypropan-2-yl)-3-oxo-2,3-dihydro-1H-isoindol-1-yl]oxy}methyl)cyclopropane-1-carbonitrile

To a solution of5-chloro-2-{[(1R)-1-(4-chlorophenyl)-1-[(1-cyanocyclopropyl)methoxy]-7-fluoro-5-(2-hydroxypropan-2-yl)-3-oxo-2,3-dihydro-1H-isoindol-2-yl]methyl}benzoicacid (Example 79) (233 mg, 0.4 mmol) in THF (10 mL) were addedtriethylamine (0.17 mL, 1.2 mmol) and isobutyl chloroformate (0.08 mL,0.6 mmol) and the reaction mixture was stirred for 1 h. Water (0.1 mL)was added followed by NaBH₄ (0.045 g, 1.2 mmol) in small portions.Stirred for 1 h, water (10 mL) was added and the product was extractedwith EtOAc. The crude product was purified on Silica, eluted withpetrol-EtOAc 0-80% to afford the title compound (150 mg, 66%).

1H NMR (400 MHz, DMSO-d6): 7.82 (1H, d), 7.53 (1H, dd), 7.37-7.22 (5H,m), 7.14-7.03 (2H, m), 5.37 (1H, s), 5.21 (1H, t), 4.54-4.36 (3H, m),4.33 (1H, d), 3.02 (1H, d), 2.80 (1H, d), 1.48 (6H, s), 1.23-1.13 (2H,m), 0.78-0.68 (1H, m), 0.61-0.52 (1H, m). MS(ES+) m/z 472 [3[M-CN(c-Pr)CH₂O)]⁺.

Examples 73 and 74:1-({[(1R)-2-[(4-chloro-2-methanesulfonylphenyl)methyl]-1-(4-chlorophenyl)-7-fluoro-5-[1-hydroxy-1-(1-methyl-1H-pyrazol-4-yl)ethyl]-3-oxo-2,3-dihydro-1H-isoindol-1-yl]oxy}methyl)cyclopropane-1-carboxamide

(*Both Isomers at Position Shown)

Step 1:2-(4-Chlorobenzoyl)-3-fluoro-5-(hydroxy(1-methyl-1H-pyrazol-4-yl)methyl)benzoicacid

A 5 litre round bottom flask fitted with an overhead stirrer was chargedwith 5-bromo-2-(4-chlorobenzoyl)-3-fluorobenzoic acid (100 g, 0.28 mol)and anhydrous THF (1.5 L). The solution was cooled to −3° C. and asolution of methyl magnesium chloride (2.15M in THF, 130 mL, 0.279 mol)was added dropwise at such a rate that the internal temperature remainedbelow −1° C. (25 min). On complete addition, the mixture was stirred at0° C. for 15 min then cooled to −78° C. A solution of n-butyllithium(2.2M in hexanes, 152 mL; 0.33 mol) was added dropwise over 30 min atsuch a rate so that the internal temperature remained below −70° C. Oncomplete addition the mixture was stirred at └78° C. for 30 min. Asolution of 1-methyl-1H-pyrazole-4-carboxaldehyde (39.7 g, 0.36 mol) inanhydrous THF (500 mL) was added dropwise over 20 min at such a rate sothat the internal temperature remained below −70° C. On completeaddition the mixture was stirred at −78° C. for 15 min, the cooling bathremoved and the mixture allowed to reach RT. The mixture was quenchedwith 1 M HCl, the pH adjusted to 1-2 and extracted with EtOAc (2×500mL). Combined organics were dried (MgSO₄) and the solvent evaporated.The residue was divided into four equal portions and each portionchromatographed on silica gel (300 g) eluting with 0-20% MeOH in DCMgradient to afford the title compound as a colourless solid (48.33 g,44.5%). Impure fractions were pooled, evaporated and chromatographed toafford a further quantity of title compound (11.05 g, 10.2%). MS:[M+H]⁺=389

Step 2:2-(4-Chlorobenzoyl)-3-fluoro-5-(1-methyl-1H-pyrazole-4-carbonyl)benzoicacid

To a stirred mixture of2-(4-chlorobenzoyl)-3-fluoro-5-(hydroxy(1-methyl-1H-pyrazol-4-yl)methyl)benzoicacid (20 g, 51.48 mmol) in EtOAc (86 mL) at 0° C. was added 10% aqueousKBr (29.83 mL, 25 mmol) followed by TEMPO (0.82 g, 5.23 mmol). To thisstirred mixture was added a solution of sodium hydrogen carbonate (5.40g, 64.25 mmol) and sodium hypochlorite (89 mL, 5-20% aqueous solution exFisher, catalogue number S/5040/PB17) in water (47 mL) at such a rate sothat the reaction temperature remained below 5° C. Addition was stoppedupon complete oxidation as indicated by LCMS (approximately half of thesolution was required). The reaction was quenched by addition of diluteaqueous sodium sulphite solution and the mixture extracted with EtOAc(4×500 mL). Combined organics were dried (MgSO₄) and the solvent removedunder reduced pressure to give the title compound as a pale orange solid(15.27 g, 76%). The aqueous layer was acidified with 2 M HCl andextracted with EtOAc (500 mL). The organics were dried (MgSO₄) and thesolvent removed under reduced pressure to give a further quantity of thetitle compound (3.44 g, 17%). MS:[M+H]⁺=387.

Step 3:2-(4-Chloro-2-(methylsulfonyl)benzyl)-3-(4-chlorophenyl)-4-fluoro-3-hydroxy-6-(1-methyl-1H-pyrazole-4-carbonyl)isoindolin-1-one

2-(4-Chlorobenzoyl)-3-fluoro-5-(1-methyl-1H-pyrazole-4-carbonyl)benzoicacid (18.20 g, 46.55 mmol) and(4-chloro-2-(methylsulfonyl)phenyl)methanamine (Example 35, step 3)(19.4 g, 88.30 mmol) were stirred in DMF (90 mL) at RT under nitrogen.HATU (26.80 g, 70.53 mmol) was added and the reaction mixture stirred atRT for 1.25 h. The reaction mixture was diluted with water, sat. aq.NaHCO₃ solution and EtOAc. The layers were separated and the aqueous wasextracted with EtOAc. The combined organics were washed with 4% LiCl aq.solution, dried (MgSO₄), filtered and concentrated in vacuo. The residuewas purified using a 340 g SNAP column eluting with EtOAc in iso-hexanes(0 to 100%) to give the title 8.8 g, 32% yield. MS: [M+H]⁺=587.

Step 4:(R)-1-(((2-(4-Chloro-2-(methylsulfonyl)benzyl)-1-(4-chlorophenyl)-7-fluoro-5-(1-methyl-1H-pyrazole-4-carbonyl)-3-oxoisoindolin-1-yl)oxy)methyl)cyclopropanecarboxamide

The title compound was prepared from2-(4-chloro-2-(methylsulfonyl)benzyl)-3-(4-chlorophenyl)-4-fluoro-3-hydroxy-6-(1-methyl-1H-pyrazole-4-carbonyl)isoindolin-1-one(2.0 g, 3.40 mmol) in a similar manner to that described in preparation10. The product was separated using chiral SFC. Slowest eluting isomer.MS: [M+H]⁺=685.

Step 5:1-({[(1R)-2-[(4-chloro-2-methanesulfonylphenyl)methyl]-1-(4-chlorophenyl)-7-fluoro-5-[1-hydroxy-1-(1-methyl-1H-pyrazol-4-yl)ethyl]-3-oxo-2,3-dihydro-1H-isoindol-1-yl]oxy}methyl)cyclopropane-1-carboxamide

(R)-1-(((1-(4-Chlorophenyl)-2-((5-chloropyridin-2-yl)methyl)-7-fluoro-5-(1-methyl-1H-pyrazole-4-carbonyl)-3-oxoisoindolin-1-yl)oxy)methyl)cyclopropanecarbonitrile(620 mg, 0.90 mmol) was stirred in THF (5 mL) at −15° C. under nitrogen.MeMgCl (2.15M in THF, 0.91 mL, 1.96 mmol) was added dropwise forming anorange solution and then stirred for 10 mins at this temperature. Thereaction was quenched with sat. aq. NH₄Cl solution, water was then addedand the reaction was warmed to RT. The aqueous was extracted with DCM(2×50 mL) and the combined organics were dried (phase separator) andconcentrated in vacuo. The residue was purified using a 25 g SNAPcolumn, eluting with MeOH in DCM (0 to 5%). Fractions containing thetitle compound were concentrated in vacuo and the compound was separatedusing chiral SFC.

Example 73: *faster eluting isomer. ¹H NMR (400 MHz, CDCl₃) 7.90 (1H,d), 7.82 (1H, d), 7.53-7.49 (1H, m), 7.42 (1H, s), 7.37-7.33 (2H, m),7.25-7.18 (5H, m), 6.52-6.52 (1H, m), 5.42-5.42 (1H, m), 5.04-4.92 (2H,m), 3.90 (3H, s), 3.36 (1H, d), 2.99 (3H, s), 2.91 (1H, d), 2.32 (1H,s), 1.94 (3H, s), 1.32-1.20 (2H, m), 0.53-0.46 (1H, m), 0.39-0.33 (1H,m); MS: [M+H]⁺=701.

Example 74: *slower eluting isomer. ¹H NMR (400 MHz, CDCl₃) 7.89 (1H,d), 7.82 (1H, s), 7.55-7.50 (1H, m), 7.41 (1H, s), 7.37-7.32 (2H, m),7.25-7.17 (5H, m), 6.52-6.52 (1H, m), 5.42-5.42 (1H, m), 5.04-4.94 (2H,m), 3.91 (3H, s), 3.36 (1H, d), 3.00 (3H, s), 2.93 (1H, d), 2.34 (1H,s), 1.94 (3H, s), 1.32-1.21 (2H, m), 0.54-0.47 (1H, m), 0.42-0.36 (1H,m); MS: [M+H]⁺=701.

Example 75 and 76:(3R)-2-[(4-chloro-2-methanesulfonylphenyl)methyl]-3-(4-chlorophenyl)-4-fluoro-6-[1-hydroxy-1-(1-methyl-1H-pyrazol-4-yl)ethyl]-3-[(1-hydroxycyclopropyl)methoxy]-2,3-dihydro-1H-isoindol-1-one

(*Both Isomers at Position Shown)

Step 1:(R)-2-(4-Chloro-2-(methylsulfonyl)benzyl)-3-(4-chlorophenyl)-4-fluoro-3-((1-hydroxycyclopropyl)methoxy)-6-(1-methyl-1H-pyrazole-4-carbonyl)isoindolin-1-one

The title compound was prepared from2-(4-chloro-2-(methylsulfonyl)benzyl)-3-(4-chlorophenyl)-4-fluoro-3-hydroxy-6-(1-methyl-1H-pyrazole-4-carbonyl)isoindolin-1-one(2.0 g, 3.4 mmol) in a similar manner to that described in preparation12. The product was separated using chiral SFC. Slowest eluting isomer.MS: [M+H]⁺=658.

Step 2:(3R)-2-[(4-chloro-2-methanesulfonylphenyl)methyl]-3-(4-chlorophenyl)-4-fluoro-6-[1-hydroxy-1-(1-methyl-1H-pyrazol-4-yl)ethyl]-3-[(1-hydroxycyclopropyl)methoxy]-2,3-dihydro-1H-isoindol-1-one

The title compound was prepared from(R)-2-(4-chloro-2-(methylsulfonyl)benzyl)-3-(4-chlorophenyl)-4-fluoro-3-((1-hydroxycyclopropyl)methoxy)-6-(1-methyl-1H-pyrazole-4-carbonyl)isoindolin-1-one(255 mg, 0.39 mmol) in a similar manner to that described in Examples 73and 74, step 5. The product was separated using chiral SFC.

Example 75: *slower eluting isomer. ¹H NMR (400 MHz, CDCl₃) 7.84 (1H,d), 7.80 (1H, d), 7.45 (1H, dd), 7.40 (1H, s), 7.34-7.20 (5H, m), 7.08(2H, d), 5.22 (1H, d), 5.02 (1H, d), 3.90 (3H, s), 3.34 (1H, d), 3.24(1H, s), 3.03 (3H, s), 2.90 (1H, d), 2.27 (1H, s), 1.93 (3H, s),0.93-0.80 (2H, m), 0.63-0.56 (1H, m), 0.43-0.37 (1H, m); MS: [M+H]+=674.

Example 76: *faster eluting isomer. ¹H NMR (400 MHz, CDCl₃) 7.84 (1H,d), 7.81 (1H, d), 7.45 (1H, dd), 7.40 (1H, d), 7.33-7.21 (5H, m), 7.08(2H, d), 5.21 (1H, d), 5.01 (1H, d), 3.90 (3H, s), 3.32 (1H, d), 3.21(1H, s), 3.02 (3H, s), 2.91 (1H, d), 2.28 (1H, s), 1.93 (3H, s),0.93-0.80 (2H, m), 0.62-0.55 (1H, m), 0.43-0.36 (1H, m); MS: [M+H]+=674.

Examples 77 and 78:(3R)-2-[(4-chloro-2-methanesulfonylphenyl)methyl]-3-(4-chlorophenyl)-4-fluoro-6-[2-hydroxy-1-(4-methylpiperazin-1-yl)propan-2-yl]-3-{[1-(hydroxymethyl)cyclopropyl]methoxy}-2,3-dihydro-1H-isoindol-1-one

The title compounds were prepared using methods similar to thosedescribed in Example 43.

Example 77: *fast running isomer: ¹H NMR (400 MHz, CDCl3) 7.91 (1H, d),7.77 (1H, d), 7.46 (1H, dd), 7.35 (1H, dd), 7.29-7.28 (2H, m), 7.22 (1H,d), 7.17 (2H, d), 5.00 (2H, d), 4.40 (1H, s) 3.83 (1H, d), 3.35 (1H, d),3.27 (1H, d), 3.04 (3H, s), 2.80 (1H, d), 2.71 (2H, dd), 2.53-2.37 (8H,m), 2.25 (3H, s), 2.01-2.01 (1H, m), 1.51 (3H, s), 0.50 (2H, dd),0.49-0.37 (1H, m), 0.21 (1H, d). MS [M+H]⁺=720.

Example 78: *slow running isomer: ¹H NMR (400 MHz, CDCl3) 7.91 (1H, d),7.76 (1H, d), 7.48 (1H, dd), 7.34 (1H, dd), 7.28 (2H, d), 7.21-7.16 (3H,m), 5.00 (2H, s), 4.47 (1H, d), 3.82 (1H, d), 3.37 (1H, d), 3.26 (1H,d), 3.04 (3H, s), 2.81 (1H, d), 2.73-2.67 (2H, m), 2.52 (2H, s), 2.37(6H, s), 2.25 (3H, s), 2.00-2.00 (1H, m), 1.51 (3H, s), 0.52-0.37 (3H,m), 0.21-0.17 (1H, m). MS [M+H]⁺=720.

Example 79:5-chloro-2-{[(1R)-1-(4-chlorophenyl)-1-[(1-cyanocyclopropyl)methoxy]-7-fluoro-5-(2-hydroxypropan-2-yl)-3-oxo-2,3-dihydro-1H-isoindol-2-yl]methyl}benzoicacid

Step 1:2-(2-Bromo-4-chlorobenzyl)-3-(4-chlorophenyl)-4-fluoro-3-hydroxy-6-(2-hydroxypropan-2-yl)isoindolin-1-one

Starting from Preparation 46 and (2-bromo-4-chlorophenyl)methanamine(Example 33, step 1) (1.3 g, 6.24 mmol), the title compound was preparedusing methods similar to Example 35, step 4 to afford2-(2-bromo-4-chlorobenzyl)-3-(4-chlorophenyl)-4-fluoro-3-hydroxy-6-(2-hydroxypropan-2-yl)isoindolin-1-oneas a colourless solid (2.15 g, 64%). MS [M+H]⁺=538.

Step 2:1-(((2-(2-Bromo-4-chlorobenzyl)-1-(4-chlorophenyl)-7-fluoro-3-oxo-5-(prop-1-en-2-yl)isoindolin-1-yl)oxy)methyl)cyclopropanecarbonitrile

The title compound was prepared from2-(2-bromo-4-chlorobenzyl)-3-(4-chlorophenyl)-4-fluoro-3-hydroxy-6-(2-hydroxypropan-2-yl)isoindolin-1-one(2.1 g, 3.9 mmol) and 1-(hydroxymethyl)cyclopropanecarbonitrile (3.42 g,9.6 mmol) using the method of Preparation 10 to furnish (1.7 g, 71%). MS[M+H]⁺=599.

Step 3:(R)-1-(((2-(2-Bromo-4-chlorobenzyl)-1-(4-chlorophenyl)-7-fluoro-5-(2-hydroxypropan-2-yl)-3-oxoisoindolin-1-yl)oxy)methyl)cyclopropanecarbonitrile

Step 3 was performed in an analogous fashion to Example 2 to give thetitle compound as a racemate (1.6 g). Purification by SFC gave the titlecompound as the fast running isomer. MS [M+H]⁺=617.

Step 4:5-chloro-2-{[(1R)-1-(4-chlorophenyl)-1-[(1-cyanocyclopropyl)methoxy]-7-fluoro-5-(2-hydroxypropan-2-yl)-3-oxo-2,3-dihydro-1H-isoindol-2-yl]methyl}benzoicacid

Step 4 was performed in an analogous fashion to Example 33, Step 5.Purification by preparative HPLC afforded(R)-5-chloro-2-((1-(4-chlorophenyl)-7-fluoro-1-((1-(hydroxymethyl)cyclopropyl)methoxy)-5-(2-hydroxypropan-2-yl)-3-oxoisoindolin-2-yl)methyl)benzoicacid (305 mg, 62%). ¹H NMR (400 MHz, DMSO) 7.84 (1H, s), 7.67 (1H, d),7.58 (1H, s), 7.56 (1H, s), 7.41 (1H, dd), 7.32-7.22 (5H, m), 4.90 (1H,d), 4.79 (1H, d), 3.16 (1H, d), 2.84 (1H, d), 1.48 (6H, s), 1.27-1.15(2H, m), 0.86-0.79 (1H, m), 0.69-0.62 (1H, m), OH not observed. MS[M+H]⁺=583.

Examples 80 and 81:(3R)-2-[(4-chloro-2-methanesulfonylphenyl)methyl]-3-(4-chlorophenyl)-4-fluoro-6-[1-hydroxy-1-(1-methylpiperidin-4-yl)ethyl]-3-{[1-(hydroxymethyl)cyclopropyl]methoxy}-2,3-dihydro-1H-isoindol-1-one

(*Both Isomers at Position Shown)

Steps 1 and 2 were performed using procedures similar to those describedin Examples 73 and 74; but using tert-butyl4-formylpiperidine-1-carboxylate instead of1-methyl-1H-pyrazole-4-carboxaldehyde. Also, Bu₂Mg was used in place ofmethylmagnesium chloride.

Step 3:5-(1-(1-(tert-Butoxycarbonyl)piperidin-4-yl)-1-hydroxyethyl)-2-(4-chlorobenzoyl)-3-fluorobenzoicacid

To a RB flask containing5-(1-(tert-butoxycarbonyl)piperidine-4-carbonyl)-2-(4-chlorobenzoyl)-3-fluorobenzoicacid (15.57 g, 31.7 mmol), under N₂, was added THF (300 mL) and cooledto −10° C. MeMgCl (34.5 mL, 79.4 mmol, 2.3M in THF) was added over aperiod of 5 mins. Immediately after the completion of the addition, LCMSanalysis showed complete conversion of the starting material. Thereaction was quenched with 1 M HCl (200 mL). The reaction was extractedwith EtOAc (2×200 mL), dried with MgSO₄, filtered and conc. in vacuo.The crude material was purified by column chromatography, BiotageIsolera, 340 g cartridge 0%-60% EtOAc (0.1% formic acid) in DCM (0.1%formic acid) to afford5-(1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1-hydroxyethyl)-2-(4-chlorobenzoyl)-3-fluorobenzoicacid as an off white foam (15.1 g, 93%). Purification by chiralpreparative LCMS.

* Fast running isomer (Isomer A): MS: [M−H]⁻=504, [α]_(D) ²⁰=+28.7 (c1.9, MeOH)

* Slow running isomer (Isomer B): MS: [M−H]⁻=504, [α]_(D) ²⁰=−27.8 (c1.8, MeOH)

Step 4:2-(4-Chlorobenzoyl)-3-fluoro-5-(1-hydroxy-1-(piperidin-4-yl)ethyl)benzoicacid hydrochloride

(−)-5-(1-(1-(tert-Butoxycarbonyl)piperidin-4-yl)-1-hydroxyethyl)-2-(4-chlorobenzoyl)-3-fluorobenzoicacid (Isomer B) (6.09 g, 12.0 mmol) was stirred in 4N HCl in dioxane (70mL) at rt for 10 min. The orange solution was concentrated in vacuoyielding2-(4-chlorobenzoyl)-3-fluoro-5-(1-hydroxy-1-(piperidin-4-yl)ethyl)benzoicacid hydrochloride (Isomer B) as an orange solid (6.88 g) which was usedin the next step without further purification. MS: [M+H]⁺=406.

In a similar manner(+)-5-(1-(1-(tert-Butoxycarbonyl)piperidin-4-yl)-1-hydroxyethyl)-2-(4-chlorobenzoyl)-3-fluorobenzoicacid (Isomer A) (7.50 g, 14.8 mmol) furnished2-(4-chlorobenzoyl)-3-fluoro-5-(1-hydroxy-1-(piperidin-4-yl)ethyl)benzoicacid hydrochloride (Isomer A) which was used in the next step withoutfurther purification. MS: [M+H]⁺=406.

Step 5:2-(4-Chlorobenzoyl)-3-fluoro-5-(1-hydroxy-1-(1-methylpiperidin-4-yl)ethyl)benzoicacid

(−)-2-(4-Chlorobenzoyl)-3-fluoro-5-(1-hydroxy-1-(piperidin-4-yl)ethyl)benzoicacid hydrochloride (Isomer B) (6.88 g, ca. 12.0 mmol) was stirred inMeOH (100 mL) at rt under nitrogen and formaldehyde solution (37% wt inwater, 24 mmol, 1.95 mL) was added. The orange solution was stirred atRT for 5 min and NaBH₃CN (14.4 mmol, 905 mg) was added. The yellowsolution was stirred at RT for 1 d after which time a colourless solidhad precipitated. The mixture was concentrated in vacuo to give2-(4-chlorobenzoyl)-3-fluoro-5-(1-hydroxy-1-(1-methylpiperidin-4-yl)ethyl)benzoicacid (Isomer B) as a yellow solid (6 g) which was used in the next stepwithout further purification.

In a similar manner(+)-2-(4-chlorobenzoyl)-3-fluoro-5-(1-hydroxy-1-(piperidin-4-yl)ethyl)benzoicacid hydrochloride (Isomer A) (6.00 g, ca. 14.8 mmol) furnished2-(4-chlorobenzoyl)-3-fluoro-5-(1-hydroxy-1-(1-methylpiperidin-4-yl)ethyl)benzoicacid (Isomer A) which was used in the next step without furtherpurification. MS: [M+H]⁺=419.9.

Step 6:2-(4-Chloro-2-(methylsulfonyl)benzyl)-3-(4-chlorophenyl)-4-fluoro-3-hydroxy-6-(1-hydroxy-1-(1-methylpiperidin-4-yl)ethyl)isoindolin-1-one

Starting from(−)-2-(4-chlorobenzoyl)-3-fluoro-5-(1-hydroxy-1-(1-methylpiperidin-4-yl)ethyl)benzoicacid (Isomer B) (2 g, 4 mmol), Step 6 was performed in a similar fashionto Example 35, Step 4 to give2-(4-chloro-2-(methylsulfonyl)benzyl)-3-(4-chlorophenyl)-4-fluoro-3-hydroxy-6-(1-hydroxy-1-(1-methylpiperidin-4-yl)ethyl)isoindolin-1-one(Isomer B), 939 mg, 38% as a pale orange solid. MS: [M+H]⁺=621

In a similar manner,(+)-2-(4-Chlorobenzoyl)-3-fluoro-5-(1-hydroxy-1-(1-methylpiperidin-4-yl)ethyl)benzoicacid (Isomer A) (1.55 g, ca. 3.70 mmol) furnished2-(4-chloro-2-(methylsulfonyl)benzyl)-3-(4-chlorophenyl)-4-fluoro-3-hydroxy-6-(1-hydroxy-1-(1-methylpiperidin-4-yl)ethyl)isoindolin-1-one(Isomer A), 1.05 g, 46%. MS: [M+H]⁺=621.

Step 7:(3R)-2-[(4-chloro-2-methanesulfonylphenyl)methyl]-3-(4-chlorophenyl)-4-fluoro-6-[1-hydroxy-1-(1-methylpiperidin-4-yl)ethyl]-3-{[1-(hydroxymethyl)cyclopropyl]methoxy}-2,3-dihydro-1H-isoindol-1-one

Using(−)-2-(4-chloro-2-(methylsulfonyl)benzyl)-3-(4-chlorophenyl)-4-fluoro-3-hydroxy-6-(1-hydroxy-1-(1-methylpiperidin-4-yl)ethyl)isoindolin-1-one(Isomer B) (847 mg, 1.36 mmol), Step 7 was performed in a similarfashion to Example 41, step 1 to give 366 mg of2-(4-chloro-2-(methylsulfonyl)benzyl)-3-(4-chlorophenyl)-4-fluoro-6-(1-hydroxy-1-(1-methylpiperidin-4-yl)ethyl)-3-((1-(hydroxymethyl)cyclopropyl)methoxy)isoindolin-1-one(Isomer B) as a pale yellow solid which was further purified usingpreparative HPLC and separated by chiral SFC to yield Example 80 (55 mg,the later running isomer)

Example 80 ¹H NMR (400 MHz, CDCl3) 7.91 (1H, d), 7.72 (1H, d), 7.46-7.42(1H, m), 7.36 (1H, dd), 7.30 (2H, d), 7.24-7.17 (3H, m), 5.06-4.96 (2H,m), 3.80 (1H, d), 3.38 (1H, d), 3.24 (1H, d), 3.03 (3H, s), 2.92 (2H,dd), 2.78 (1H, d), 2.35-2.35 (3H, m), 2.25 (3H, s), 1.96-1.83 (2H, m),1.74 (1H, d), 1.61 (3H, s), 1.49-1.35 (3H, m), 0.50 (2H, s), 0.49-0.38(1H, m), 0.23 (1H, d); MS: [M+H]⁺=705.4.

In a similar manner(+)-2-(4-chloro-2-(methylsulfonyl)benzyl)-3-(4-chlorophenyl)-4-fluoro-3-hydroxy-6-(1-hydroxy-1-(1-methylpiperidin-4-yl)ethyl)isoindolin-1-one(Isomer A) (787 mg, 1.27 mmol) furnished 138 mg2-(4-chloro-2-(methylsulfonyl)benzyl)-3-(4-chlorophenyl)-4-fluoro-6-(1-hydroxy-1-(1-methylpiperidin-4-yl)ethyl)-3-((1-(hydroxymethyl)cyclopropyl)methoxy)isoindolin-1-one(Isomer A) which was further purified using preparative HPLC andseparated by chiral SFC to yield Example 81 (8 mg, the later runningisomer).

Example 81 ¹H NMR (400 MHz, CDCl3) 8.40 (1H, s), 7.91 (1H, d), 7.70 (1H,d), 7.45 (1H, dd), 7.35 (1H, dd), 7.30 (2H, d), 7.23 (1H, d), 7.19 (2H,d), 5.00 (2H, s), 3.73-3.67 (1H, m), 3.44 (1H, d), 3.35-3.23 (2H, m),3.14 (1H, d), 3.03 (3H, s), 2.88 (1H, d), 2.51 (3H, s), 2.28-2.24 (3H,m), 1.94-1.77 (4H, m), 1.62 (3H, s), 1.40-1.31 (1H, m), 0.50 (2H, dd),0.48-0.38 (1H, m), 0.26 (1H, d); MS: [M+H]⁺=705.

Example 82:(3R)-2-{[4-chloro-2-(dimethylphosphoryl)phenyl]methyl}-3-(4-chlorophenyl)-4-fluoro-3-{[1-(hydroxymethyl)cyclopropyl]methoxy}-6-(2-hydroxypropan-2-yl)-2,3-dihydro-1H-isoindol-1-one

Starting from 5-bromo-2-(4-chlorobenzoyl)-3-fluorobenzoic acid andPreparation 47: (2-(aminomethyl)-5-chlorophenyl)dimethylphosphine oxide,the title compound was prepared using procedures similar to thosedescribed in preparation 9, preparation 10. Example 21 Step 3 andExample 41 Step 3; in a sequential manner.

*fast running isomer: ¹H NMR (400 MHz, CDCl₃) 7.81 (1H, d), 7.45 (1H,dd), 7.31 (2H, d), 7.19-7.13 (2H, m), 7.10-7.06 (3H, m), 5.36 (1H, d),5.09 (2H, d), 4.37 (1H, dd), 3.84 (1H, d), 2.97 (1H, d), 2.18 (1H, d),1.89 (1H, s), 1.77 (3H, d), 1.74 (3H, d), 1.65 (3H, s), 1.64 (3H, s),0.58-0.42 (3H, m), 0.27-0.22 (1H, m). [M+H]+=620.

Examples 83 and 84:(3R)-2-[(4-chloro-2-methanesulfonylphenyl)methyl]-3-(4-chlorophenyl)-4-fluoro-6-[hydroxy(oxan-4-yl)methyl]-3-{[1-(hydroxymethyl)cyclopropyl]methoxy}-2,3-dihydro-1H-isoindol-1-one

(*Both Isomers at Position Shown)

Step 1 and 2: Starting from Preparation 48, Steps 1 and 2 were performedusing procedures similar to those described in Examples 73 and 74 Step 3and Step 4, but using 1,1-bis(hydroxymethyl)cyclopropane instead of1-(hydroxymethyl)cyclopropane-1-carboxamide. MS:[M-1-(cyclopropane-1,1-diyldimethanol]+=574

Step 3:(3R)-2-[(4-chloro-2-methanesulfonylphenyl)methyl]-3-(4-chlorophenyl)-4-fluoro-6-[hydroxy(oxan-4-yl)methyl]-3-{[1-(hydroxymethyl)cyclopropyl]methoxy}-2,3-dihydro-1H-isoindol-1-one

The product from Step 2 (300 mg, 0.44 mmol) was dissolved in methanol (1mL) under nitrogen at RT with stirring. Sodium borohydride (25 mg, 0.66mmol) was added to the reaction mixture and the reaction was allowed tostir at room temperature for 10 min then quenched and diluted withwater. The reaction was extracted with DCM. The combined organicportions were dried (MgSO₄) and concentrated under reduced pressure. Thecrude residue was purified on a 10 g SNAP silica cartridge, eluting withethyl acetate in isohexane (10 to 100%). Fractions containing pureproduct were concentrated under reduced pressure to yield a white solid(247 mg) which was separated using chiral SFC.

Example 83 *slower eluting isomer. ¹H NMR (400 MHz, CDCl3) 7.91 (1H, d),7.72 (1H, s), 7.35 (1H, dd), 7.28-7.26 (2H, m), 7.24-7.16 (4H, m),5.06-4.96 (2H, m), 4.55 (1H, dd), 4.05-3.93 (2H, m), 3.80 (1H, dd),3.42-3.23 (4H, m), 3.04 (3H, s), 2.78 (1H, d), 2.11 (1H, d), 2.01-1.96(1H, m), 1.94-1.84 (1H, m), 1.78 (1H, d), 1.54-1.37 (2H, m), 1.29-1.21(1H, m), 0.54-0.48 (2H, m), 0.46-0.38 (1H, m), 0.22 (1H, d); MS:[M+H]+=678.

Example 84 *faster eluting isomer. ¹H NMR (400 MHz, CDCl3) 7.91 (1H, d),7.67 (1H, s), 7.35 (1H, dd), 7.30-7.26 (3H, m), 7.24-7.17 (3H, m),5.06-4.96 (2H, m), 4.56 (1H, dd), 4.06-3.94 (2H, m), 3.82 (1H, dd),3.40-3.25 (4H, m), 3.03 (3H, s), 2.75 (1H, d), 2.16 (1H, d), 2.03-1.99(1H, m), 1.93-1.83 (1H, m), 1.78 (1H, d), 1.55-1.37 (2H, m), 1.28 (1H,d), 0.54-0.47 (2H, m), 0.46-0.40 (1H, m), 0.23 (1H, d); MS: [M+H]+=678.

Example 85 and 86:1-({[(1R)-2-[(4-chloro-2-methanesulfonylphenyl)methyl]-1-(4-chlorophenyl)-7-fluoro-5-[1-hydroxy-1-(oxan-4-yl)ethyl]-3-oxo-2,3-dihydro-1H-isoindol-1-yl]oxy}methyl)cyclopropane-1-carboxamide

(*Both Isomers at Position Shown)

Using2-(4-chloro-2-(methylsulfonyl)benzyl)-3-(4-chlorophenyl)-4-fluoro-3-hydroxy-6-(tetrahydro-2H-pyran-4-carbonyl)isoindolin-1-one(Examples 83 and 84; Step 1), the title compound was prepared usingmethods similar to those described in Preparation 12 (using1-(hydroxymethyl)cyclopropanecarboxamide instead of1,1-bis(hydroxymethyl)cyclopropane) and Examples 73 and 74 Step 5.

Example 85 *slower eluting isomer. ¹H NMR (400 MHz, CDCl3) 7.90 (1H, d),7.77 (1H, d), 7.50-7.46 (1H, m), 7.36 (1H, dd), 7.28-7.18 (5H, m),6.52-6.52 (1H, m), 5.42-5.42 (1H, m), 5.06-4.95 (2H, m), 4.07-3.94 (2H,m), 3.41-3.28 (3H, m), 3.00 (3H, s), 2.93 (1H, d), 1.91-1.84 (1H, m),1.82 (1H, s), 1.63 (3H, s), 1.56 (1H, s), 1.53-1.40 (2H, m), 1.33-1.22(3H, m), 0.53-0.47 (1H, m), 0.42-0.35 (1H, m); MS: [M+H]+=705.

Example 86 *faster eluting isomer. ¹H NMR (400 MHz, CDCl3) 7.91 (1H, s),7.81 (1H, s), 7.44 (1H, d), 7.36 (1H, d), 7.26-7.19 (5H, m), 6.52-6.52(1H, m), 5.42 (1H, s), 5.05-4.95 (2H, m), 4.06-3.96 (2H, m), 3.39-3.35(3H, m), 3.00 (3H, s), 2.92 (1H, d), 1.91-1.84 (2H, m), 1.67-1.56 (4H,m), 1.47 (2H, s), 1.26-1.24 (3H, m), 0.51 (1H, s), 0.37-0.37 (1H, m);MS: [M+H]+=705

Example 87:5-chloro-2-{[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[1-hydroxy-1-(1-methylpiperidin-4-yl)ethyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]methyl}benzoicacid

(Example Isolated as a Single Isomer at the Position Shown*)

Step 1: tert-Butyl4-[1-[2-[(2-bromo-4-chloro-phenyl)methyl]-1-(4-chlorophenyl)-7-fluoro-1-hydroxy-3-oxo-isoindolin-5-yl]-1-hydroxy-ethyl]piperidine-1-carboxylate

Prepared in a similar manner to that described for Example 35, step 4from(−)-5-[1-(1-tert-butoxycarbonyl-4-piperidyl)-1-hydroxy-ethyl]-2-(4-chlorobenzoyl)-3-fluoro-benzoicacid and (2-bromo-4-chlorophenyl)methanamine. MS: [M−H₂O]⁺=691.

Step 2:2-[(2-Bromo-4-chloro-phenyl)methyl]-3-(4-chlorophenyl)-4-fluoro-6-[1-hydroxy-1-(4-piperidyl)ethyl]-3-methoxy-isoindolin-1-one

Prepared in a similar manner to that described in Preparation 10 fromtert-butyl4-[1-[2-[(2-bromo-4-chloro-phenyl)methyl]-1-(4-chlorophenyl)-7-fluoro-1-hydroxy-3-oxo-isoindolin-5-yl]-1-hydroxy-ethyl]piperidine-1-carboxylateand methanol. MS: [M+H]⁺=623.

Step 3:2-[(2-Bromo-4-chloro-phenyl)methyl]-3-(4-chlorophenyl)-4-fluoro-6-[1-hydroxy-1-(1-methyl-4-piperidyl)ethyl]-3-methoxy-isoindolin-1-one

The title compound was prepared from2-[(2-bromo-4-chloro-phenyl)methyl]-3-(4-chlorophenyl)-4-fluoro-6-[1-hydroxy-1-(4-piperidyl)ethyl]-3-methoxy-isoindolin-1-onein analogous fashion to Example 81, step 5. MS: [M+H]⁺=637.

Step 4:5-Chloro-2-[[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[1-hydroxy-1-(1-methyl-4-piperidyl)ethyl]-1-methoxy-3-oxo-isoindolin-2-yl]methyl]benzoicacid

Prepared in a similar manner to that described for Example 33, step 5from2-[(2-bromo-4-chloro-phenyl)methyl]-3-(4-chlorophenyl)-4-fluoro-6-[1-hydroxy-1-(1-methyl-4-piperidyl)ethyl]-3-methoxy-isoindolin-1-one.¹H NMR (400 MHz, CDCl3) 7.87 (1H, s), 7.53 (1H, d), 7.49 (1H, d), 7.31(2H, d), 7.24 (2H, d), 7.19 (1H, d), 7.11 (1H, dd), 4.96 (1H, d), 4.81(1H, d), 3.47 (1H, d), 3.36-3.32 (1H, m), 2.87 (3H, s), 2.87-2.71 (2H,m), 2.73 (3H, s), 2.11-2.02 (1H, m), 1.99-1.90 (1H, m), 1.80-1.63 (2H,m), 1.62 (3H, s), 1.51 (1H, m). MS: [M+H]⁺=601.

Examples 88 and 89:(3S)-3-(4-chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[1-hydroxy-1-(oxan-4-yl)ethyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]propanoicacid

(*Both Isomers Separated and Isolated)

Step 1: (3S)-Ethyl3-(4-chlorophenyl)-3-(1-(4-chlorophenyl)-7-fluoro-1-hydroxy-3-oxo-5-(tetrahydro-2H-pyran-4-carbonyl)isoindolin-2-yl)propanoate

2-(4-Chlorobenzoyl)-3-fluoro-5-(tetrahydro-2H-pyran-4-carbonyl)benzoicacid (Preparation 48) (3.99 g, 10.2 mmol) was reacted with (S)-ethyl3-amino-3-(4-chlorophenyl)propanoate hydrochloride (3.5 g, 13.25 mmol)in an analogous fashion as described in Example 35, step 4 to afford thetitle compound (3.4 g, 50%) as a yellow solid. MS: [M−H]⁻=598.

Step 2: (S)-Ethyl3-(4-chlorophenyl)-3-((R)-1-(4-chlorophenyl)-7-fluoro-1-methoxy-3-oxo-5-(tetrahydro-2H-pyran-4-carbonyl)isoindolin-2-yl)propanoate

The title compound was prepared from (3S)-ethyl3-(4-chlorophenyl)-3-(1-(4-chlorophenyl)-7-fluoro-1-hydroxy-3-oxo-5-(tetrahydro-2H-pyran-4-carbonyl)isoindolin-2-yl)propanoateand methanol in a similar manner as described in Preparation 12. Thediastereoisomers were separated chiral SFC. [M+H]+=614.

Step 3:(S)-3-(4-Chlorophenyl)-3-((R)-1-(4-chlorophenyl)-7-fluoro-1-methoxy-3-oxo-5-(tetrahydro-2H-pyran-4-carbonyl)isoindolin-2-yl)propanoicacid

The title compound was prepared from (S)-ethyl3-(4-chlorophenyl)-3-((R)-1-(4-chlorophenyl)-7-fluoro-1-methoxy-3-oxo-5-(tetrahydro-2H-pyran-4-carbonyl)isoindolin-2-yl)propanoatein an analogous fashion as described in Preparation 40. [M+H]⁺=586.

Step 4:(3S)-3-(4-chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[1-hydroxy-1-(oxan-4-yl)ethyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]propanoicacid

The title compound was prepared from(S)-3-(4-chlorophenyl)-3-((R)-1-(4-chlorophenyl)-7-fluoro-1-methoxy-3-oxo-5-(tetrahydro-2H-pyran-4-carbonyl)isoindolin-2-yl)propanoicacid in a similar manner to that described in Example 1 to give theracemate which was separated by chiral SFC.

Example 88: *fast running isomer ¹H NMR (400 MHz, CDCl3) 7.67 (1H, d),7.34-7.29 (1H, m), 7.03 (4H, s), 7.00 (4H, s), 4.68 (1H, dd), 4.04-3.90(2H, m), 3.68 (1H, dd), 3.36-3.24 (3H, m), 3.08 (3H, s), 1.86-1.77 (1H,m), 1.61-1.55 (4H, m), 1.47-1.36 (2H, m), 1.26-1.17 (1H, m), (OH andCO₂H not visible). [M+H]⁺=602.

Example 89: *slow running isomer ¹H NMR (400 MHz, CDCl3) 7.68 (1H, s),7.29 (1H, d), 7.03 (4H, s), 7.00 (4H, s), 4.69 (1H, dd), 4.05-3.90 (2H,m), 3.69-3.61 (1H, m), 3.37-3.24 (3H, m), 3.09 (3H, s), 1.87-1.77 (1H,m), 1.63-1.56 (4H, m), 1.50-1.37 (2H, m), 1.20 (1H, d), (OH and CO₂H notvisible). [M+H]⁺=602.

Examples 90 and 91:4-[(1R)-1-[(1R)-1-(4-Chlorophenyl)-7-fluoro-5-[1-hydroxy-1-(1-methyl-1H-imidazol-4-yl)propyl]-3-oxo-1-[(3S)-oxolan-3-yloxy]-2,3-dihydro-1H-isoindol-2-yl]-2-hydroxyethyl]benzonitrile

(*Both Isomers Separated and Isolated)

Step 1, 2 and 3: Starting from Preparations 49 and 50, Steps 1, 2 and 3were performed using procedures similar to those described in Example 73Step 3, Step 4 and Step 5, but using and (3S)-hydroxy-tetrahydrofuraninstead of 1-(hydroxymethyl)cyclopropane-1-carboxamide in Step 2 andEtMgCl instead of MeMgCl in Step 3.

Step 4:4-[(1R)-1-[(1R)-1-(4-Chlorophenyl)-7-fluoro-5-[1-hydroxy-1-(1-methyl-1H-imidazol-4-yl)propyl]-3-oxo-1-[(3S)-oxolan-3-yloxy]-2,3-dihydro-1H-isoindol-2-yl]-2-hydroxyethyl]benzonitrile

Pd(PPh₃)₄ (56 mg, 0.05 mmol) and K₂CO₃ (252 mg, 1.88 mmol) were added toa solution of4-[(1R)-1-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[1-hydroxy-1-(1-methyl-1H-imidazol-4-yl)propyl]-3-oxo-1-[(3S)-oxolan-3-yloxy]-2,3-dihydro-1H-isoindol-2-yl]-2-(prop-2-en-1-yloxy)ethyl]benzonitrile(630 mg, 0.94 mmol) in MeOH (10 mL) and the resulting mixture wasstirred at 80° C. for 2 hours. The solvent was then removed in vacuo andthe residue was purified by flash chromatography on silica gel (gradient(0-100% EtOAc in petrol). The two diastereoisomers were then separatedby chiral HPLC.

Example 90, isomer 1 (73 mg, 12% yield): 1H NMR (400 MHz, DMSO-d6): 7.90(1H, s), 7.58-7.50 (2H, m), 7.47 (2H, d), 7.18 (2H, d), 7.07-6.82 (5H,m), 5.56 (1H, s), 5.13 (1H, dd), 4.49-4.40 (1H, m), 4.35-4.24 (2H, m),4.10-3.96 (1H, m), 3.87 (1H, q), 3.69-3.62 (1H, m), 3.61 (3H, s),3.48-3.42 (1H, m), 3.20-3.08 (1H, m), 2.26-2.05 (4H, m), 0.70 (3H, t);LCMS: [M+H]⁺=631.

Example 91, isomer 2 (97 mg, 16% yield): 1H NMR (400 MHz, DMSO-d6): 7.85(1H, s), 7.61-7.51 (2H, m), 7.46 (2H, d), 7.18 (2H, d), 7.10-6.83 (5H,m), 5.56 (1H, s), 5.13 (1H, t), 4.49-4.39 (1H, m), 4.36-4.24 (2H, m),4.09-3.97 (1H, m), 3.87 (1H, q), 3.70-3.58 (4H, m), 3.43-3.37 (1H, m),3.11 (1H, dd), 2.25-2.02 (4H, m), 0.70 (3H, t); LCMS: [M+H]⁺=631.

Examples 92 and 93:4-{[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[I-hydroxy-1-(1-methyl-1H-imidazol-4-yl)propyl]-3-oxo-1-[(3S)-oxolan-3-yloxy]-2,3-dihydro-1H-isoindol-2-yl]methyl}-3-(hydroxymethyl)benzonitrile

(*Both Isomers Separated and Isolated)

The title compounds were prepared in a similar fashion as in Example 90,but using Preparation 51 instead of 49 in step 1.

Example 92: *fast running isomer ¹H NMR (400 MHz, CDCl3) 7.81 (1H, d),7.57 (1H, d), 7.45-7.38 (2H, m), 7.36 (1H, d), 7.28 (1H, d), 7.20 (4H,s), 6.83 (1H, d), 4.74-4.65 (2H, m), 4.58 (1H, dd), 4.42 (1H, d),3.85-3.70 (2H, m), 3.69 (3H, s), 3.62-3.53 (3H, m), 3.23 (1H, dd),2.75-2.66 (1H, m), 2.23-2.06 (2H, m), 1.48-1.37 (2H, m), 0.84 (3H, dd).[M+H]⁺=631.

Example 93: *slow running isomer ¹H NMR (400 MHz, CDCl3) 7.69 (1H, d),7.58-7.51 (2H, m), 7.41-7.36 (2H, m), 7.25-7.23 (1H, m), 7.19 (4H, s),6.85 (1H, d), 4.73-4.66 (2H, m), 4.58 (1H, d), 4.42 (1H, d), 3.86-3.72(2H, m), 3.70 (3H, s), 3.62-3.54 (3H, m), 3.22 (1H, dd), 2.23-2.06 (2H,m), 1.50-1.40 (2H, m), 1.27-1.08 (1H, m), 0.84 (3H, dd). [M+H]⁺=631.

Examples 94 and 95:4-{[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[1-hydroxy-1-(1-methyl-1H-imidazol-4-yl)propyl]-1-{[1-(hydroxymethyl)cyclopropyl]methoxy}-3-oxo-2,3-dihydro-1H-isoindol-2-yl]methyl}benzonitrile

(*Both Isomers Separated and Isolated)

Step 1 and 2: Starting from Preparation 50, Steps 1 and 2 were performedusing procedures similar to those described in Examples 73 Step 3 andStep 4 but using 4-(aminomethyl)benzonitrile in Step 1 and[1-(hydroxymethyl)cyclopropyl]methanol in Step 2.

Step 3:4-{[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[1-hydroxy-1-(1-methyl-1H-imidazol-4-yl)propyl]-1-{[1-(hydroxymethyl)cyclopropyl]methoxy}-3-oxo-2,3-dihydro-1H-isoindol-2-yl]methyl}benzonitrile

A solution of(R)-4-((1-(4-chlorophenyl)-7-fluoro-1-((1-(hydroxymethyl)cyclopropyl)methoxy)-5-(1-methyl-1H-imidazole-4-carbonyl)-3-oxoisoindolin-2-yl)methyl)benzonitrile)(190 mg, 0.325 mmol), in anhydrous CH₂Cl₂ (10 mL) was stirred at 0° C.under nitrogen. AlEt₃ (2.5 mL, 1M in hexanes, 2.5 mmol) was addeddrop-wise and the mixture was stirred at 0° C. for 1 h. The reaction wasquenched with sat. aq. NH₄Cl and diluted with CH₂Cl₂ (10 mL) and water(7 mL). Solids were removed by filtration and the filtrate was extractedwith CH₂Cl₂ (2×15 mL). Combined organics were dried (MgSO₄) and thesolvent evaporated. The crude residue was purified by columnchromatography, Interchim, 12 g KP-sil cartridge 0-5% MeOH in EtOAc toafford the racemate (98 mg, 49%). Chiral preparative HPLC gave the titlecompounds:

Example 94 (faster running isomer) ¹H NMR (400 MHz, CDCl3) 7.71 (1H, s),7.47 (3H, dd), 7.36 (1H, s), 7.27-7.26 (2H, m), 7.18 (4H, s), 6.84 (1H,s), 4.49 (1H, d), 4.32 (1H, d), 3.69 (3H, s), 3.53 (1H, d), 3.41 (1H,d), 2.97 (1H, d), 2.79 (1H, d), 2.24-2.07 (2H, m), 1.25 (1H, s), 0.86(3H, dd), 0.45 (2H, dd), 0.28-0.23 (1H, m), 0.15-0.09 (1H, m). MS:[M+H]⁺=615

Example 95: (slower running isomer) ¹H NMR (400 MHz, CDCl3) 7.71 (1H,s), 7.49 (3H, dd), 7.36 (1H, s), 7.28-7.27 (2H, m), 7.19 (4H, s), 6.85(1H, s), 4.51 (1H, d), 4.31 (1H, d), 3.69 (3H, s), 3.55 (1H, s),3.52-3.47 (1H, m), 3.41 (1H, dd), 2.96 (1H, d), 2.78 (1H, d), 2.22-2.06(2H, m), 0.85 (3H, dd), 0.44 (2H, dd), 0.29-0.23 (1H, m), 0.15-0.08 (1H,m). MS: [M+H]⁺=615

Examples 96 and 97:4-{[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[I-hydroxy-1-(1-methyl-1H-imidazol-4-yl)propyl]-3-oxo-1-[(3S)-oxolan-3-yloxy]-2,3-dihydro-1H-isoindol-2-yl]methyl}benzonitrile

(*Both Isomers Separated and Isolated)

The title compounds were prepared in a similar manner as in Example 94and Example 95, but using (3S)-hydroxy-tetrahydrofuran in Step 2. Chiralpreparative HPLC gave the title compounds.

Example 96: ¹H NMR (400 MHz, CDCl3) 7.70 (1H, d), 7.55-7.52 (1H, m),7.46 (2H, d), 7.36 (1H, s), 7.27-7.24 (2H, m), 7.16 (4H, s), 6.85 (1H,d), 4.50 (1H, d), 4.32 (1H, d), 3.84-3.76 (2H, m), 3.70 (3H, s),3.63-3.52 (3H, m), 3.23 (1H, dd), 2.24-2.07 (2H, m), 1.51-1.44 (2H, m),0.84 (3H, t). MS: [M+H]⁺=601

Example 97: ¹H NMR (400 MHz, CDCl3) 7.81 (1H, d), 7.48-7.42 (3H, m),7.36 (1H, s), 7.28-7.25 (2H, m), 7.17 (4H, s), 6.83 (1H, d), 4.51 (1H,d), 4.32 (1H, d), 3.82-3.75 (2H, m), 3.69 (3H, s), 3.62-3.54 (3H, m),3.25 (1H, dd), 2.23-2.07 (2H, m), 1.49-1.42 (2H, m), 0.84 (3H, t). MS:[M+H]⁺=601.

Examples 98 and 99:(3S)-3-(4-chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[1-(4-fluorooxan-4-yl)-1-hydroxyethyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]propanoicacid

(*Both Isomers Separated and Isolated)

Step 1 and 2: Ethyl(3S)-3-(4-chlorophenyl)-3-(1-(4-chlorophenyl)-7-fluoro-5-(4-fluorotetrahydro-2H-pyran-4-carbonyl)-1-hydroxy-3-oxoisoindolin-2-yl)propanoate

Starting from2-(4-chlorobenzoyl)-3-fluoro-5-(4-fluorotetrahydro-2H-pyran-4-carbonyl)benzoicacid (Preparation 53), (S)-ethyl 3-amino-3-(4-chlorophenyl)propanoatehydrochloride (Preparation 35) and MeOH, Steps 1-2 were performed byfollowing procedures similar to those described in Example 35, step 4and Preparation 10 respectively. The diastereoisomers were separatedusing chiral SFC to give ethyl(S)-3-(4-chlorophenyl)-3-((R)-1-(4-chlorophenyl)-7-fluoro-5-(4-fluorotetrahydro-2H-pyran-4-carbonyl)-1-methoxy-3-oxoisoindolin-2-yl)propanoate.MS: [M-MeOH]⁺=600.

Step 3:(S)-3-(4-Chlorophenyl)-3-((R)-1-(4-chlorophenyl)-7-fluoro-5-(4-fluorotetrahydro-2H-pyran-4-carbonyl)-1-methoxy-3-oxoisoindolin-2-yl)propanoicacid

Step 3 was performed using procedures similar to those described inPreparation 52, Step 3. MS: [M−H]⁻=602.

Step 4:(3S)-3-(4-chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[1-(4-fluorooxan-4-yl)-1-hydroxyethyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]propanoicacid

Step 4 was performed using procedures similar to those described inExample 73, Step 5.

Example 98: *fast running isomer: ¹H NMR (400 MHz, CDCl₃) 7.78 (1H, s),7.39 (1H, d), 7.04 (4H, s), 7.00 (4H, s), 4.68 (1H, dd), 3.89-3.56 (5H,m), 3.31 (1H, dd), 3.10 (3H, s), 1.98-1.60 (7H, m), 1.44 (1H, dd); COOHmissing. MS: [M+H]⁺=620.

Example 99: * Slow running isomer: ¹H NMR (400 MHz, CDCl₃) 7.79 (1H, s),7.39 (1H, d), 7.03 (4H, s), 7.00 (4H, s), 4.69 (1H, dd); 3.90-3.56 (5H,m), 3.30 (1H, dd), 3.11 (3H, s), 1.97-1.73 (3H, m), 1.73-1.63 (4H, m),1.47-1.39 (1H, m); COOH missing. MS: [M+H]⁺=620.

Example 100:(4S)-4-(4-chlorophenyl)-4-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[1-hydroxy-1-(1-methyl-1H-pyrazol-3-yl)propyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]butanoicacid

(*Prepared as a Mixture of Epimers at the Position Shown)

Starting from Preparation 65 and methyl(4S)-4-amino-4-(4-chlorophenyl)butanoate, the title compound wasprepared using procedures similar to those described in Example 99; butusing EtMgCl/ZnCl₂ instead of MeMgCl in the final step. 1H NMR (400 MHz,CDCl₃): 7.74 (1H, d), 7.49-7.44 (1H, m), 7.34 (1H, d), 7.04-7.00 (8H,m), 6.21 (1H, t), 4.23-4.15 (1H, m), 3.88 (3H, s), 3.19 (3H, d),3.11-3.02 (1H, m), 2.55-2.44 (2H, m), 2.32-2.11 (6H, m), 0.90-0.85 (4H,m). MS: [M+H]⁺=626.

Example 101 and 102:(3S)-3-(4-chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[1-(4-fluorooxan-4-yl)-1-hydroxypropyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]propanoicacid

(*Both Isomers Separated and Isolated)

Starting from(S)-3-(4-chlorophenyl)-3-((R)-1-(4-chlorophenyl)-7-fluoro-5-(4-fluorotetrahydro-2H-pyran-4-carbonyl)-1-methoxy-3-oxoisoindolin-2-yl)propanoicacid (Example 99 step 3), the title compounds were prepared usingprocedures similar to those described in Preparation 52, Step 1. Thetitle compounds, prepared as a mixture, were subsequently separatedusing chiral SFC.

Example 101: *fast running isomer: ¹H NMR (400 MHz, CDCl₃) 7.74 (1H, s),7.39 (1H, d), 7.04 (4H, s), 7.01 (4H, d), 4.68 (1H, dd), 3.86-3.57 (5H,m), 3.30 (1H, dd), 3.10 (3H, s), 2.25-2.15 (2H, m), 2.05-1.81 (3H, m),1.66-1.42 (2H, m), 0.69 (3H, t); COOH missing. MS: [M+H]⁺=634.

Example 102: * Slow running isomer: ¹H NMR (400 MHz, CDCl₃) 7.75 (1H,s), 7.37 (1H, d), 7.04 (4H, s), 7.01 (4H, s), 4.70 (1H, dd), 3.87-3.58(5H, m), 3.29 (1H, dd), 3.11 (3H, s), 2.25-2.15 (2H, m), 2.02-1.80 (3H,m), 1.71-1.51 (1H, m), 1.43 (1H, dd), 0.69 (3H, t); COOH missing. MS:[M+H]⁺=634.

Example 103 and 104:(3S)-3-(4-chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-5-(1-cyclobutyl-1-hydroxyethyl)-7-fluoro-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]propanoicacid

(*Both Isomers Separated and Isolated)

Starting from2-(4-chlorobenzoyl)-5-(cyclobutanecarbonyl)-3-fluorobenzoic acid(Preparation 55) the title compound was prepared using methods similarto those described for Example 98. Except that 2M aqueous HCl solutionwas used instead of LiOH in Step 3.

Example 103: *fast running isomer: ¹H NMR (400 MHz, CDCl₃) 7.70 (1H, s),7.31 (1H, d), 7.04-6.99 (4H, m), 6.98 (4H, s), 4.67 (1H, dd), 3.61-3.60(1H, m), 3.33-3.25 (1H, m), 3.06 (3H, s), 2.74-2.65 (1H, m), 2.05-1.93(2H, m), 1.87-1.73 (2H, m), 1.66 (1H, d), 1.56-1.54 (1H, m), 1.44 (3H,s); OH and COOH missing; MS: [M+H]⁺=572.

Example 104: * Slow running isomer: ¹H NMR (400 MHz, CDCl₃) 7.71 (1H,s), 7.29 (1H, d), 7.05-6.93 (8H, m), 4.70 (1H, dd), 3.59 (1H, s),3.22-3.17 (1H, m), 3.06 (3H, s), 2.74-2.65 (1H, m), 2.07-1.66 (5H, m),1.61-1.54 (1H, m), 1.44 (3H, s); OH and COOH missing; MS: [M+H]⁺=572.

Example 105:(3S)-3-(4-chiorophenyl)-3-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[(1S)-1-hydroxy-1-(oxan-4-yl)propyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]propanoicacid

Step 1: Ethyl(3S)-3-(4-chlorophenyl)-3-(1-(4-chlorophenyl)-7-fluoro-1-hydroxy-5-((S)-1-hydroxy-1-(tetrahydro-2H-pyran-4-yl)propyl)-3-oxoisoindolin-2-yl)propanoate

(S)-2-(4-Chlorobenzoyl)-3-fluoro-5-(1-hydroxy-1-(tetrahydro-2H-pyran-4-yl)propyl)benzoicacid (Preparation 52, 1.43 g, 3.39 mmol) was reacted with (S)-ethyl3-amino-3-(4-chlorophenyl)propanoate hydrochloride (Preparation 35, 1.16g, 4.41 mmol) in an analogous fashion as described in Example 35, step 4to afford the title compound (1.37 g, 64%) as a colourless foam. MS:[M−H]⁻=628.

Step 2: Ethyl(S)-3-(4-chlorophenyl)-3-((R)-1-(4-chlorophenyl)-7-fluoro-5-((S)-1-hydroxy-1-(tetrahydro-2H-pyran-4-yl)propyl)-1-methoxy-3-oxoisoindolin-2-yl)propanoate

The title compound was prepared from ethyl(3S)-3-(4-chlorophenyl)-3-(1-(4-chlorophenyl)-7-fluoro-1-hydroxy-5-((S)-1-hydroxy-1-(tetrahydro-2H-pyran-4-yl)propyl)-3-oxoisoindolin-2-yl)propanoate(1.3 g, 2.06 mmol) and methanol (0.83 mL, 20 mmol) in a similar manneras described in Preparation 10. The diastereoisomers were separatedusing chiral SFC giving the title compound (0.39 g) as a pale yellowfoam. MS: [M-MeOH]⁺=612.

Step 3:(3S)-3-(4-chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[(1S)-1-hydroxy-1-(oxan-4-yl)propyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]propanoicacid

The title compound was prepared from ethyl(S)-3-(4-chlorophenyl)-3-((R)-1-(4-chlorophenyl)-7-fluoro-5-((S)-1-hydroxy-1-(tetrahydro-2H-pyran-4-yl)propyl)-1-methoxy-3-oxoisoindolin-2-yl)propanoate(0.391 g, 0.6 mmol) using procedures similar to those described inPreparation 52, Step 3. The crude product was purified by preparativeHPLC to give pure title compound (80 mg) as a white solid. ¹H NMR (400MHz, CDCl₃) 7.62 (1H, d), 7.29 (1H, dd), 7.04 (4H, s), 7.00 (4H, s),4.68 (1H, dd), 4.03 (1H, dd), 3.90 (1H, dd), 3.74 (1H, dd), 3.40-3.25(3H, m), 3.09 (3H, s), 1.97-1.86 (3H, m), 1.73 (1H, d), 1.49-1.35 (2H,m), 1.07 (1H, d), 0.68 (3H, t); OH and COOH missing. MS: [M+H]⁺=616.

Starting from the appropriate chiral acid intermediate (e.g. Preparation52, Preparation 52b or Preparation 54), the following Examples wereprepared using procedures similar to those described in Example 105steps 1-3. An appropriately protected α- or β-amino acid was used inStep 1 [e.g. methyl (S)-4-amino-4-(4-chlorophenyl)butanoate or (S)-ethyl3-amino-3-(4-chlorophenyl)propanoate hydrochloride (Preparation 35)] andan appropriate alcohol (e.g. MeOH, EtOH, CD₃OH) was used in Step 2.

In some cases the product was isolated as atris(hydroxymethyl)aminomethane (TRIS) salt (by dissolving in MeOH,treated with tris(hydroxymethyl)aminomethane and evaporation).

Example 106:(3S)-3-(4-chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[(1R)-1-hydroxy-1-(oxan-4-yl)propyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]propanoicacid

¹H NMR (400 MHz, CDCl₃) 7.62 (1H, d), 7.28 (2H, d), 7.04 (4H, s), 7.01(4H, s), 4.68 (1H, dd), 4.03 (1H, dd), 3.89 (1H, dd), 3.73 (1H, dd),3.42-3.25 (3H, m), 3.10 (3H, s), 1.96-1.85 (3H, m), 1.74 (1H, d),1.49-1.36 (2H, m), 1.06 (1H, d), 0.68 (3H, t); COOH missing. MS:[M+H]⁺=616.

Example 107:(4S)-4-(4-chlorophenyl)-4-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[(1S)-1-hydroxy-1-(oxan-4-yl)propyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]butanoicacid

¹H NMR (400 MHz, CDCl₃) 7.61 (s, 1H), 7.06-7.01 (m, 4H), 6.99 (d, 2H),4.19 (dd, 1H), 4.02 (dd, 1H), 3.90 (dd, 1H), 3.40-3.24 (m, 2H), 3.19 (s,3H), 3.13-3.03 (m, 1H), 2.54-2.44 (m, 1H), 2.32-2.11 (m, 2H), 2.07-1.96(m, 1H), 1.96-1.84 (m, 3H), 1.73 (d, 3H), 1.47-1.36 (m, 3H), 1.27-1.16(m, 1H), 1.07 (d, 1H), 0.69 (dd, 2H). MS: [M+H]⁺=630.

Example 108:(4S)-4-(4-chlorophenyl)-4-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[(1R)-1-hydroxy-1-(oxan-4-yl)propyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]butanoicacid

¹H NMR (400 MHz, CDCl₃) 7.62-7.59 (3H, m), 7.41 (2H, d), 7.35 (2H, d),7.31-7.26 (3H, m), 4.09-4.00 (2H, m), 3.91 (1H, dd), 3.41-3.27 (2H, m),2.88-2.77 (1H, m), 2.51-2.42 (4H, m), 2.03-1.97 (2H, m), 1.97-1.85 (3H,m), 1.73 (1H, d), 1.48-1.38 (2H, m), 1.08 (1H, d), 0.70-0.64 (3H, m); OHand COOH missing. MS: [M+H]⁺=630.

Example 109:(4S)-4-(4-Chlorophenyl)-4-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[(1R)-1-(4-fluorooxan-4-yl)-1-hydroxypropyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]butanoicacid (tris(hydroxymethyl)aminomethane salt)

¹H NMR (400 MHz, DMSO) 7.76 (1H, s), 7.48 (1H, d), 7.18-7.12 (4H, m),7.10-7.02 (4H, m), 4.25 (1H, dd), 3.88 (1H, dd), 3.72 (1H, dd),3.56-3.50 (1H, m), 3.47-3.39 (1H, m), 3.37 (6H, s), 3.18 (3H, s),2.84-2.73 (1H, m), 2.48-2.38 (1H, m), 2.26-2.17 (1H, m), 2.05-1.88 (6H,m), 1.07-0.99 (1H, m), 0.63 (3H, t); 7 protons missing (OH×4, NH2 andCOOH). MS: [M+H]⁺=648.

Example 110:(3S)-3-(4-chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[(1R)-1-(4-fluorooxan-4-yl)-1-hydroxypropyl]-1-trideuteromethoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]propanoicacid

¹H NMR (400 MHz, CDCl₃) 7.61 (1H, s), 7.26 (1H, d), 7.07-6.99 (8H, m),4.19 (1H, dd), 3.51-3.43 (1H, m), 3.19 (3H, s), 3.14-3.04 (1H, m),2.53-2.44 (1H, m), 2.30-1.85 (7H, m), 1.67-1.60 (1H, m), 1.31-1.07 (5H,m), 0.66 (3H, dd). MS: [M+H]⁺=637.

Example 111:(3S)-3-(4-chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-1-ethoxy-7-fluoro-5-[(1R)-1-(4-fluorooxan-4-yl)-1-hydroxypropyl]-3-oxo-2,3-dihydro-1H-isoindol-2-yl]propanoicacid

¹H NMR (400 MHz, CDCl₃) 7.73 (1H, s), 7.36 (1H, d), 7.06-7.00 (8H, m),4.69 (1H, dd), 3.86-3.75 (3H, m), 3.66-3.57 (2H, m), 3.30-3.12 (3H, m),2.26-2.13 (2H, m), 2.02-1.82 (3H, m), 1.67-1.40 (3H, m), 1.28 (3H, dd),0.68 (3H, dd). MS: [M+H]⁺=637.

Example 113:(4S)-4-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[(1R)-1-(4-fluorooxan-4-yl)-1-hydroxypropyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]-4-(4-methoxyphenyl)butanoicacid

¹H NMR (400 MHz, CDCl3) 7.73 (1H, s), 7.35 (1H, d), 7.05-6.93 (6H, m),6.58 (2H, d), 4.16 (1H, dd), 3.81 (2H, d), 3.73 (3H, s), 3.66-3.58 (2H,m), 3.17 (3H, s), 3.11-3.10 (1H, m), 2.51-2.42 (1H, m), 2.31-2.28 (4H,m), 2.27-2.13 (3H, m), 1.69-1.44 (2H, m), 0.69 (3H, dd); COOH notobserved. MS: [M+H]⁺=644.

Example 114:(4S)-4-(4-chlorophenyl)-4-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-{1-hydroxy-1-[trans-4-hydroxycyclohexyl]propyl}-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]butanoicacid

Starting from the single isomer of2-(4-chlorobenzoyl)-3-fluoro-5-(1-hydroxy-1-trans-4-hydroxycyclohexyl)propyl)benzoicacid (Preparation 64, Step 3), the title compound was prepared byfollowing procedures similar to those described in Example 105. ¹H NMR(400 MHz, CDCl₃) 7.61 (1H, s), 7.26 (1H, d), 7.07-6.99 (8H, m), 4.19(1H, dd), 3.51-3.43 (1H, m), 3.19 (3H, s), 3.14-3.04 (1H, m), 2.53-2.44(1H, m), 2.30-1.85 (7H, m), 1.67-1.60 (1H, m), 1.31-1.07 (5H, m), 0.66(3H, dd), exchangeable not observed. MS: [M+H]⁺=644.

Example 115:2-(5-chloro-2-{[1-(4-chlorophenyl)-7-fluoro-5-[(1R)-1-(4-fluorooxan-4-yl)-1-hydroxypropyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]methyl}phenoxy)aceticacid (tris(hydroxymethyl)aminomethane salt)

Starting from(R)-2-(4-chlorobenzoyl)-3-fluoro-5-(1-(4-fluorotetrahydro-2H-pyran-4-yl)-1-hydroxypropyl)benzoicacid (Preparation 54) and ethyl2-[2-(aminomethyl)-5-chlorophenoxy]acetate hydrochloride (Preparation63), the title compound was prepared by following procedures similar tothose described in Example 105. ¹H NMR (400 MHz, DMSO-d₆-D₂O): 7.71 (1H,s), 7.40 (1H, d), 7.26-7.17 (4H, m), 6.91 (1H, d), 6.67 (1H, dd), 6.50(1H, d), 4.38 (2H, s), 4.19-4.00 (2H, m), 3.84-3.74 (1H, m), 3.66 (1H,dd), 3.46 (7H, s), 2.84 (3H, s), 2.19-2.03 (1H, m), 1.99-1.74 (4H, m),1.14 (1H, d), 1.04-0.95 (1H, m), 0.56 (3H, t). MS:[M+H]⁺=650.

Example 116:5-chloro-2-{[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[(1S)-1-hydroxy-1-(oxan-4-yl)propyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]methyl}benzoicacid

Step 1 and Step 2: Starting from(−)-(S)-2-(4-chlorobenzoyl)-3-fluoro-5-(1-hydroxy-1-(tetrahydro-2H-pyran-4-yl)propyl)benzoicacid (Preparation 52), (2-bromo-4-chlorophenyl)methanamine (Example 33,Step 1) and MeOH, Step 1 and Step 2 were performed by followingprocedures similar to those described in Example 35, step 4 andPreparation 10 respectively Chiral separation using supercritical fluidchromatography gave(R)-2-(2-bromo-4-chlorobenzyl)-3-(4-chlorophenyl)-4-fluoro-6-((S)-1-hydroxy-1-(tetrahydro-2H-pyran-4-yl)propyl)-3-methoxyisoindolin-1-one.MS: [M+H]⁺=638

Step 3:5-chloro-2-{[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[(1S)-1-hydroxy-1-(oxan-4-yl)propyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]methyl}benzoicacid

The title compound was prepared in a similar manner to that describedfor Example 33, step 5. ¹H NMR (400 MHz, DMSO) 7.78 (1H, s), 7.69 (1H,s), 7.50 (1H, d), 7.37-7.31 (5H, m), 7.24 (1H, s), 4.98 (1H, s),4.94-4.81 (2H, m), 3.98-3.93 (1H, m), 3.82 (1H, dd), 3.40-3.30 (1H, m),3.28-3.21 (1H, m), 2.88 (3H, s), 2.05-1.90 (3H, m), 1.73 (1H, d),1.48-1.30 (2H, m), 1.02 (1H, d), 0.65 (3H, t), COOH missing. MS:[M+H]⁺=602.

Starting from the appropriate chiral acid intermediate (e.g. Preparation52, Preparation 54), the following Examples were prepared usingprocedures similar to those described in Example 116 steps 1-3. Theappropriate benzylamine [e.g. (2-bromo-4-chlorophenyl)methanamine,Preparation 58 or Preparation 59] was used in Step 1 and an appropriatealcohol used in Step 2. In some cases the product was isolated as atris(hydroxymethyl)aminomethane (TRIS) salt (by dissolving in MeOH,treated with tris(hydroxymethyl)aminomethane and evaporation).Purification by preparative HPLC gave the products as single isomers,with the configuration shown.

Example 117:5-chloro-2-{[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[(1R)-1-hydroxy-1-(oxan-4-yl)propyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]methyl}benzoicacid

Prepared from(+)-(R)-2-(4-chlorobenzoyl)-3-fluoro-5-(1-hydroxy-1-(tetrahydro-2H-pyran-4-yl)propyl)benzoicacid (Preparation 52b). ¹H NMR (400 MHz, CDCl₃) 7.73 (2H, d), 7.30-7.18(6H, m, overlapping CHCl3), 7.14 (1H, d), 5.12 (1H, d), 4.64 (1H, d),4.01 (1H, dd), 3.84 (1H, dd), 3.37-3.19 (2H, m), 2.81 (3H, s), 1.98-1.71(4H, m), 1.71 (1H, d), 1.45-1.33 (2H, m), 1.05-0.99 (1H, m), 0.64 (3H,t). COOH missing MS: [M+H]⁺=602.

Example 118:5-chloro-2-{[(1R)-1-(4-chlorophenyl)-1-ethoxy-7-fluoro-5-[(1S)-1-hydroxy-1-(oxan-4-yl)propyl]-3-oxo-2,3-dihydro-1H-isoindol-2-yl]methyl}benzoicacid-(tris(hydroxymethyl)aminomethane salt)

¹H NMR (400 MHz, CDCl₃) 7.79 (1H, s), 7.50 (1H, s), 7.21 (2H, d),7.08-7.00 (2H, m), 6.82 (1H, d), 5.02 (2H, s), 4.59-4.59 (3H, m),3.97-3.94 (1H, m), 3.85-3.81 (1H, m), 3.73 (6H, s), 3.33-3.17 (2H, m),3.06-2.94 (2H, m), 1.84-1.59 (4H, m), 1.43-1.34 (2H, m), 1.00 (4H, dd),0.55 (3H, t), one exchangeable proton not observed. MS: [M+H]⁺=616.

Example 119:2-{[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[(1R)-1-(4-fluorooxan-4-yl)-1-hydroxypropyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]methyl}-5-methylbenzoicacid

¹H NMR (400 MHz, CDCl3) 7.78 (1H, s), 7.69 (1H, s), 7.40-7.31 (4H, m),7.26-7.19 (3H, m), 4.99 (1H, d, J=15.4 Hz), 4.83 (1H, d, J=15.4 Hz),3.86-3.77 (2H, m), 3.68-3.57 (2H, m), 2.80 (3H, s), 2.34 (3H, s),2.25-2.14 (1H, m), 2.00-1.80 (2H, m), 1.70-1.42 (3H, m), 1.26 (1H, s),0.69 (3H, dd); COOH not observed. [M+H]⁺=601

Example 120:2-{[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[(1R)-1-(4-fluorooxan-4-yl)-1-hydroxypropyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]methyl}-5-methoxybenzoicacid-tris(hydroxymethyl)aminomethane salt

¹H NMR (400 MHz, CDCl3) 7.83 (1H, s), 7.32-7.18 (5H, m), 7.13-7.13 (1H,m), 6.95 (1H, d), 6.68 (1H, d), 4.92 (2H, d), 4.65 (1H, d), 3.82-3.78(1H, m), 3.72 (6H, s), 3.61-3.48 (4H, m), 2.87 (3H, s), 2.62 (1H, s),2.08-2.00 (1H, m), 1.94-1.60 (6H, m), 1.26-1.16 (1H, m), 0.55 (3H, s).[M+H]+=616

Example 121:2-(5-chloro-2-{[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[(1S)-1-hydroxy-1-(oxan-4-yl)propyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]methyl}phenyl)-2-methylpropanoicacid (tris(hydroxymethyl)aminomethane salt)

Step 1: Methyl2-(5-chloro-2-(((R)-1-(4-chlorophenyl)-7-fluoro-5-((S)-1-hydroxy-1-(tetrahydro-2H-pyran-4-yl)propyl)-1-methoxy-3-oxoisoindolin-2-yl)methyl)phenyl)-2-methylpropanoate

A diastereomeric mixture at C-3 of2-(2-bromo-4-chlorobenzyl)-3-(4-chlorophenyl)-4-fluoro-6-((S)-1-hydroxy-1-(tetrahydro-2H-pyran-4-yl)propyl)-3-methoxyisoindolin-1-one(1 g, prepared as in Example 116, Step 2 (omitting chiral separation),methyl trimethylsilyl dimethylketene acetal (820 mg, 4.71 mmol), zincfluoride (486.6 mg, 4.71 mmol) and di-u-bromobis(tri-t-butylphosphonino)dipalladium (I) {[P(t-Bu)₃]PdBr} (STREM) (243 mg, 0.314 mmol) wereplaced in a round bottomed flask under nitrogen then degassed DMF (20mL) was added. The reaction was degassed with nitrogen for a further 5minutes then heated (using a pre-heated stirrer block set at 70° C.) for18 h. The reaction was allowed to cool and degassed for 10 min. Thereaction was charged with further methyl trimethylsilyl dimethylketeneacetal (858 mg, 4.92 mmol), zinc fluoride (500 mg, 4.84 mmol) and{[P(t-Bu)₃]PdBr} (250 mg, 0.32 mmol) then heated (using a pre-heatedstirrer block set at 70° C.) for 4 h. The reaction was allowed to cooland then the DMF was removed under reduced pressure. Water (20 mL) andEtOAc (50 mL) was added and the resulting black suspension was filtered.The layers of the filtrate were separated and the organics retained. Theaqueous portion was extracted with EtOAc (20 mL) then the combinedorganic extracts were dried (MgSO₄) and concentrated under reducedpressure to afford a black residue (1.5 g). The residue was dissolved inTHF (15 mL) at RT with stirring and 1M TBAF solution in THF (7.75 ml)was added. The reaction was stirred for 15 min at RT. The reaction wasdiluted with EtOAc (60 mL) and washed with water (20 mL). The organicportion was dried (MgSO₄) and concentrated under reduced pressure toafford a black residue (1.4 g). The crude material was purified bycolumn chromatography using an isocratic gradient of diethyl ether 75%in isohexane, to afford a foam (540 mg). The two diastereoisomers wereseparated by chiral SFC to yield the title compound as the fast runningisomer (300 mg). MS [M-C3 Methoxy]⁺=626.1

Step 2:2-(5-chloro-2-{[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[(1S)-1-hydroxy-1-(oxan-4-yl)propyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]methyl}phenyl)-2-methylpropanoicacid

Methyl2-(5-chloro-2-(((R)-1-(4-chlorophenyl)-7-fluoro-5-((S)-1-hydroxy-1-(tetrahydro-2H-pyran-4-yl)propyl)-1-methoxy-3-oxoisoindolin-2-yl)methyl)phenyl)-2-methylpropanoate(300 mg) was dissolved in THF (22 mL) then a solution on lithiumhydroxide monohydrate (109.1 mg, 4.5 mmol) in water (7.5 mL) andmethanol (4.5 mL) was added at RT with stirring. The reaction was heatedat 65° C. for four days then at 75° C. for one day. The reaction wasallowed to cool then the volatiles were removed under reduced pressure.The resulting emulsion was diluted with ether (50 mL) and water (20 mL)and the pH adjusted (by the addition of 2M aqueous HCl) to facilitateextraction of the product into the organic layer. The organic portionwas passed through a phase separation cartridge and the volatiles wereremoved under reduced pressure to afford a crude foam (200 mg). Thecrude material was purified by column chromatography, eluting with agradient of 0-100% diethyl ether in isohexane followed by washing with100% EtOAc with 0.1% formic acid additive to afford a crude mixture (70mg). Further purification by Prep HPLC afforded the title compound (46mgs) as a colourless foam. The product was then isolated as theTRIS-salt by dissolving in MeOH, treating with TRIS and evaporating. ¹HNMR (400 MHz, CDCl₃) 7.74 (1H, s), 7.31 (1H, s), 7.31-7.28 (1H, m), 7.24(3H, s), 7.17 (2H, d), 7.08 (1H, d), 7.01 (1H, dd), 4.50-4.37 (2H, m),4.04 (1H, dd), 3.92 (1H, dd), 3.43 (6H, s), 3.39-3.28 (2H, m), 2.96 (3H,s), 2.73 (1H, dd), 2.01-1.89 (3H, m), 1.73 (1H, s), 1.52-1.50 (6H, m),1.14-1.07 (1H, m), 0.72 (3H, dd) (7 exchangeable protons not observed).MS [M+H]⁺=644.

Example 122:2-(5-chloro-2-{[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[(1S)-1-hydroxy-1-(oxan-4-yl)propyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]methyl}phenyl)aceticacid (tris(hydroxymethyl)aminomethane salt)

Step 1: Methyl2-(5-chloro-2-(((R)-1-(4-chlorophenyl)-7-fluoro-5-((S)-1-hydroxy-1-(tetrahydro-2H-pyran-4-yl)propyl)-1-methoxy-3-oxoisoindolin-2-yl)methyl)phenyl)acetate

1-(tert-Butyldimethylsilyloxy)-1-methoxyethene (1270.3 mg, 6.75 mmol),zinc fluoride (697.5 mg, 6.75 mmol), tri-t-butylphosphine (136 mg, 0.67mmol) and bis(dibenzylideneacetone) palladium(0) (193.9 mg, 0.337 mmol)were divided evenly between two reaction tubes. A degassed solution of adiastereomeric mixture at C-3 of2-(2-bromo-4-chlorobenzyl)-3-(4-chlorophenyl)-4-fluoro-6-((S)-1-hydroxy-1-(tetrahydro-2H-pyran-4-yl)propyl)-3-methoxyisoindolin-1-one(860 mg, 1.35 mmol, prepared as in Example 116 Step 2 omitting chiralseparation) in DMF (20 mL) was divided evenly between the two reactiontubes. The mixture in each tube was degassed with nitrogen for a further30 s prior to being sealed then stirred with heating (using a pre-heatedstirrer block set at 70° C.) for 18 h. The reaction was allowed to coolto RT and DMF was removed under reduced pressure. Water (20 mL) andEtOAc (50 mL) was added and the resulting black suspension filtered. Thelayers of the filtrate were separated and the organics retained. Theaqueous portion was extracted with EtOAc (20 mL) then the combinedorganic extracts were dried (MgSO₄) and concentrated under reducedpressure to afford a black residue (1.5 g). The crude material waspurified by column chromatography with a gradient of 50-90% diethylether in isohexane to afford a colourless foam (510 mg). The twodiastereoisomers were separated by chiral SFC to yield the titlecompound as the fast running isomer (140 mg, 33% yield). MS [M-C3methoxy]⁺=598.1

Step 2:2-(5-chloro-2-{[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[(1S)-1-hydroxy-1-(oxan-4-yl)propyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]methyl}phenyl)aceticacid (tris(hydroxymethyl)aminomethane salt)

Step 2 was performed using conditions similar to those described inPreparation 52 Step 3 to give the title compound. ¹H NMR (400 MHz,CDCl₃) 7.78 (1H, s), 7.25-7.18 (4H, m), 7.14 (1H, d), 7.06-6.97 (3H, m),4.70 (1H, d), 4.21 (1H, d), 4.00 (1H, d), 3.86 (1H, d), 3.70 (1H, d),3.59 (6H, s), 3.54 (1H, d), 3.38-3.22 (3H, m), 2.74 (3H, s), 1.89-1.78(2H, m), 1.69 (1H, d), 1.48-1.34 (2H, m), 1.05 (1H, d), 0.64 (3H, dd),seven exchangeable protons not observed. MS [M+H]⁺=616

Example 123:2-(5-chloro-2-{[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[(1R)-1-hydroxy-1-(oxan-4-yl)propyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]methyl}phenyl)aceticacid

The title compound was prepared in a similar fashion to Example 122, butstarting from(+)-(R)-2-(4-chlorobenzoyl)-3-fluoro-5-(1-hydroxy-1-(tetrahydro-2H-pyran-4-yl)propyl)benzoicacid (prepared in a similar fashion to Preparation 52). ¹H NMR (400 MHz,CDCl₃) 7.67 (s, 2H), 7.30-7.10 (m, 7H), 4.71 (d, 1H), 4.15 (d, 1H), 4.03(dd, 1H), 3.88 (dd, 1H), 3.80 (d, 1H), 3.72 (d, 1H), 3.37 (t, 1H), 3.25(t, 1H), 2.72 (s, 3H), 1.95-1.82 (m), 1.71 (d, 1H), 1.48-1.32 (m, 2H),1.10-0.98 (m, 1H), 0.91-0.80 (m, 1H), 0.65 (t, 3H). MS [M-OMe⁻]⁺=584

Example 124:(2S,3S)-3-(4-chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[(1S)-1-hydroxy-1-(oxan-4-yl)propyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]-2-methylpropanoicacid

Step 1: Prop-2-en-1-yl(2S,3S)-3-(4-chlorophenyl)-3-[1-(4-chlorophenyl)-7-fluoro-1-hydroxy-5-[(1S)-1-hydroxy-1-(oxan-4-yl)propyl]-3-oxo-2,3-dihydro-1H-isoindol-2-yl]-2-methylpropanoate

To a solution of(S)-2-(4-chlorobenzoyl)-3-fluoro-5-(1-hydroxy-1-(tetrahydro-2H-pyran-4-yl)propyl)benzoicacid (Preparation 52) (0.686 g, 1.6 mmol), prop-2-en-1-yl(2S,3S)-3-amino-3-(4-chlorophenyl)-2-methylpropanoate (Preparation 62)(0.54 g, 2.12 mmol) and diisopropylethylamine (0.83 mL, 4.8 mmol) in DMF(15 mL) was added HATU (0.91 g, 2.4 mmol) and the reaction mixture wasstirred for 2 hrs. Water was added and extracted with ethyl acetate. Theorganic phase was washed with saturated NaHCO₃, brine, dried and thesolvent evaporated. The crude product was purified by chromatography toafford the title compound (0.75 g, 72%). MS: [M−H]⁻=654.

Step 2: Prop-2-en-1-yl(2S,3S)-3-(4-chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[(1S)-1-hydroxy-1-(oxan-4-yl)propyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]-2-methylpropanoate

The title compound was prepared from ethyl(2S,3S)-3-(4-chlorophenyl)-3-[1-(4-chlorophenyl)-7-fluoro-1-hydroxy-5-[(1S)-1-hydroxy-1-(oxan-4-yl)propyl]-3-oxo-2,3-dihydro-1H-isoindol-2-yl]-2-methylpropanoateand methanol in a similar manner as described in Preparation 10, butusing MeOH instead of 1,1-bis(hydroxymethyl)cyclopropane. Thediastereoisomers were separated by chiral SFC, the title compound wasthe faster eluting isomer. MS: [M+H]⁺=670.

Step 3:(2S,3S)-3-(4-Chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[(1S)-1-hydroxy-1-(oxan-4-yl)propyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]-2-methylpropanoicacid

The title compound was prepared from prop-2-en-1-yl(2S,3S)-3-(4-chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[(1S)-1-hydroxy-1-(oxan-4-yl)propyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]-2-methylpropanoatein an analogous fashion as described in Example 90, step 4. 1H NMR (400MHz, DMSO-d6): 12.56-12.00 (1H, m), 7.71 (1H, s), 7.42 (1H, d), 7.02(4H, d), 6.88 (3H, d), 4.91 (1H, s), 4.23 (1H, d), 3.99-3.85 (2H, m),3.75 (1H, dd), 3.25-3.10 (5H, m), 2.02-1.90 (1H, m), 1.90-1.78 (2H, m),1.67 (1H, d), 1.43-1.17 (6H, m), 0.95 (1H, d), 0.58 (3H, t).MS:[M+H]⁺=630.

Example 124a:(2S,3S)-3-(4-chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[(1S)-1-hydroxy-1-(oxan-4-yl)propyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]-2-methylpropanoicacid (tris(hydroxymethyl)aminomethane salt)

Example 124 was dissolved in EtOH and 1 mol. eq. oftris(hydroxymethyl)aminomethane was added. The solvent was removed invacuo to give a colourless solid. ¹H NMR (500 MHz, DMSO-d6) δ 7.69 (s,1H), 7.39 (d, J=10.7 Hz, 1H), 7.01 (broad s, 4H), 6.96-6.88 (m, 4H),4.92 (broad s, 1H), 4.34-4.22 (m, 1H), 3.88 (dd, J=10.9, 4.2 Hz, 1H),3.74 (dd, J=11.1, 4.2 Hz, 1H), 3.71-3.61 (m, 1H), 3.29 (s, 6H),3.33-3.22 (m, 1H), 3.21-3.14 (m, 1H), 3.13 (s, 3H), 1.94 (tt, J=12.2,3.6 Hz, 1H), 1.89-1.78 (m, 2H), 1.66 (d, J=12.8 Hz, 1H), 1.41-1.24 (m,2H), 1.19 (d, J=6.8 Hz, 3H), 0.93 (d, J=13.2 Hz, 1H), 0.57 (t, J=7.3 Hz,3H). MS:[M+H]⁺=630.

Example 125 and 126:(3S)-3-(4-chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-7-fluoro-1-[(3-fluorooxetan-3-yl)methoxy]-5-(2-hydroxybutan-2-yl)-3-oxo-2,3-dihydro-1H-isoindol-2-yl]propanoicacid (*Both Isomers Separated and Isolated)

Step 1: Ethyl(S)-3-((R)-5-bromo-1-(4-chlorophenyl)-7-fluoro-1-((3-fluorooxetan-3-yl)methoxy)-3-oxoisoindolin-2-yl)-3-(4-chlorophenyl)propanoate

The title compound was prepared from (3S)-ethyl3-(5-bromo-1-(4-chlorophenyl)-1-hydroxy-3-oxoisoindolin-2-yl)-3-(4-chlorophenyl)propanoate(Preparation 36, 7.19 g, 12.7 mmol) and (3-fluorooxetan-3-yl)methanol(4.00 g, 38 mmol) in a similar manner as described in Preparation 10.The diastereoisomers were separated by column chromatography elutingwith DCM. The title compound was obtained as a colourless solid (1.93g). MS: [M-(3-fluorooxetan-3-yl)methanol]⁺=550.

Step 2: Step 2 was performed by using procedures similar to thosedescribed in Example 21 Step 3, to give ethyl(S)-3-((R)-5-acetyl-1-(4-chlorophenyl)-7-fluoro-1-((3-fluorooxetan-3-yl)methoxy)-3-oxoisoindolin-2-yl)-3-(4-chlorophenyl)propanoate(1.29 g) as a yellow solid. MS: [M-(3-fluorooxetan-3-yl)methanol]⁺=512.

Step 3:(S)-3-((R)-5-Acetyl-1-(4-chlorophenyl)-7-fluoro-1-((3-fluorooxetan-3-yl)methoxy)-3-oxoisoindolin-2-yl)-3-(4-chlorophenyl)propanoicacid

The title compound was prepared from ethyl(S)-3-((R)-5-acetyl-1-(4-chlorophenyl)-7-fluoro-1-((3-fluorooxetan-3-yl)methoxy)-3-oxoisoindolin-2-yl)-3-(4-chlorophenyl)propanoate(1.19 g, 1.92 mmol) using procedures similar to those described inPreparation 52, Step 3 The crude product was obtained as a sticky orangesolid (1.26 g). MS: [M+H]⁺=590.

Step 4:(3S)-3-(4-chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-7-fluoro-1-[(3-fluorooxetan-3-yl)methoxy]-5-(2-hydroxybutan-2-yl)-3-oxo-2,3-dihydro-1H-isoindol-2-yl]propanoicacid

The title compound was prepared by using procedures similar to thosedescribed in Example 41, Step 3; except using ethylmagnesium chlorideinstead of (tetrahydro-2H-pyran-4-yl)magnesium chloride.

Example 125: *fast running isomer: ¹H NMR (400 MHz, CDCl₃) 7.73 (1H, d),7.38 (1H, dd), 7.04-6.94 (8H, m), 4.93-4.72 (3H, m), 4.68-4.59 (2H, m),3.73-3.62 (2H, m), 3.52-3.36 (2H, m), 1.89-1.80 (2H, m), 1.59 (3H, s),0.80 (3H, dd); OH and COOH missing. MS: [M+H]⁺=620.

Example 126: * Slow running isomer: ¹H NMR (400 MHz, CDCl₃) 7.74 (1H,s), 7.37 (1H, d), 7.02-6.95 (8H, m), 4.93-4.59 (5H, m), 3.72-3.63 (2H,m), 3.52-3.37 (2H, m), 1.89-1.81 (2H, m), 1.58 (3H, s), 0.82 (3H, dd);OH and COOH missing. MS: [M+H]⁺=620.

Examples 127 and 128:(3S)-3-(4-chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[1-hydroxy-1-(pyridin-2-yl)propyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]propanoicacid

(*Both Isomers Separated and Isolated)

Step 1: Ethyl(3S)-3-(4-chlorophenyl)-3-[1-(4-chlorophenyl)-7-fluoro-1-hydroxy-3-oxo-5-(pyridine-2-carbonyl)-2,3-dihydro-1H-isoindol-2-yl]propanoate

To a stirred solution of2-(4-chlorobenzoyl)-3-fluoro-5-(pyridine-2-carbonyl)benzoic acid(preparation 61) (0.48 g, 1.25 mmol), (S)-ethyl3-amino-3-(4-chlorophenyl)propanoate hydrochloride (0.47 g, 1.87 mmol)and diisopropyl ethylamine (0.9 mL, 5.0 mmol) in DMF (15 mL) was addedN-propylphosphonic acid anhydride, cyclic trimer (50% w/w, 1.211 mL,1.87 mmol) and the reaction mixture was stirred for 1 h. Water was addedand the product was extracted with ethyl acetate. The crude product waspurified by chromatography, eluted with petrol ether-ethyl acetate 0-50%to afford the title compound (0.36 g, 39%). MS: [M+H]⁺=384.

Step 2: Ethyl(3S)-3-(4-chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-7-fluoro-1-methoxy-3-oxo-5-(pyridine-2-carbonyl)-2,3-dihydro-1H-isoindol-2-yl]propanoate

The title compound was prepared from ethyl(3S)-3-(4-chlorophenyl)-3-[1-(4-chlorophenyl)-7-fluoro-1-hydroxy-3-oxo-5-(pyridine-2-carbonyl)-2,3-dihydro-1H-isoindol-2-yl]propanoateand methanol in a similar manner as described in Preparation 10. Thediastereoisomers were separated by column chromatography [M+H]⁺=607.

Step 3:(3S)-3-(4-Chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-7-fluoro-1-methoxy-3-oxo-5-(pyridine-2-carbonyl)-2,3-dihydro-1H-isoindol-2-yl]propanoicacid

The title compound was prepared from ethyl(3S)-3-(4-chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-7-fluoro-1-methoxy-3-oxo-5-(pyridine-2-carbonyl)-2,3-dihydro-1H-isoindol-2-yl]propanoatein an analogous fashion as described in Preparation 40. [M+H]⁺=579.

Step 4:(3S)-3-(4-chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[1-hydroxy-1-(pyridin-2-yl)propyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]propanoicacid

To a solution of(3S)-3-(4-chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-7-fluoro-1-methoxy-3-oxo-5-(pyridine-2-carbonyl)-2,3-dihydro-1H-isoindol-2-yl]propanoicacid (0.5 g, 0.86 mmol) in THF 10 mL) was added ZnCl₂ (1.7 mL, 0.5 M inTHF, 0.85 mmol) and the mixture was stirred for 30 mins, cooled to −30°C. and EtMgCl (1.29 mL, 2 M in THF, 2.58 mmol) was added and stirred for30 mins. Saturated NH₄Cl solution was added, acidified to pH=4.5 andextracted with ethyl acetate. The diastereoisomers were separated bychiral SFC.

Example 127: fast running isomer

¹H NMR (400 MHz, DMSO-d₆): 12.36 (1H, s), 8.61-8.55 (1H, m), 7.85 (1H,d), 7.82-7.70 (2H, m), 7.63-7.56 (1H, m), 7.30-7.23 (1H, m), 7.17-7.04(4H, m), 7.04-6.88 (4H, m), 6.08 (1H, s), 4.60 (1H, dd), 3.46 (1H, dd),3.18 (1H, dd), 3.08-3.00 (3H, m), 2.44-2.34 (1H, m), 2.34-2.24 (1H, m),0.71 (3H, t). MS: [M+H]⁺=609.

Example 128: slow running isomer

¹H NMR (400 MHz, DMSO-d₆): 12.29 (1H, d), 8.59-8.53 (1H, m), 7.86 (1H,d), 7.83-7.70 (2H, m), 7.59 (1H, dd), 7.28-7.22 (1H, m), 7.17-7.05 (4H,m), 7.05-6.92 (4H, m), 6.07 (1H, s), 4.61 (1H, dd), 3.49-3.41 (1H, m),3.22-3.09 (1H, m), 3.03 (3H, s), 2.41 (1H, dd), 2.34-2.26 (1H, m), 0.71(3H, t).

MS: [M+H]⁺=609.

Example 129:(3R)-2-[(4-chloro-2-methanesulfonylphenyl)methyl]-3-(4-chlorophenyl)-4-fluoro-6-[1-(4-fluoropiperidin-4-yl)-1-hydroxypropyl]-3-methoxy-2,3-dihydro-1H-isoindol-1-one(Example Isolated as a Single Isomer at the Position Shown*)

Starting from(−)-5-(1-(1-(tert-butoxycarbonyl)-4-fluoropiperidin-4-yl)-1-hydroxypropyl)-2-(4-chlorobenzoyl)-3-fluorobenzoicacid (preparation 57) and (4-chloro-2-(methylsulfonyl)phenyl)methanamine(Example 35, step 3), the title compound was prepared using proceduressimilar to those described in Example 87 (Steps 1-2). ¹H NMR (400 MHz,CDCl3) 7.93 (1H, d), 7.78 (1H, s), 7.49 (1H, d), 7.45-7.38 (2H, m), 7.32(2H, d), 7.24 (2H, d), 4.96 (2H, q), 3.02 (3H, s), 2.96 (3H, s),2.95-2.83 (4H, m), 2.26-2.16 (2H, m), 2.09-1.95 (2H, m), 1.86-1.62 (3H,m), 1.44-1.25 (1H, m), 0.71 (3H, dd); MS [M+H]+=653.

Example 130:4-{[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[(1S)-1-hydroxy-1-(1-methylpiperidin-4-yl)propyl]-3-oxo-1-[cis-3-hydroxycyclobutoxy]-2,3-dihydro-1H-isoindol-2-yl]methyl}benzonitrile

Starting from(S)-5-(1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1-hydroxypropyl)-2-(4-chlorobenzoyl)-3-fluorobenzoicacid (Preparation 60), 4-aminomethylbenzonitrile andcis-3-((tert-butyldimethylsilyl)oxy)cyclobutan-1-ol, the title compoundwas prepared using procedures similar to those described in Example 87(Steps 1-3). Purification by chiral SFC gave the title compound (slowrunning isomer): ¹H NMR (400 MHz, CDCl₃) 7.62 (1H, d), 7.50 (2H, d),7.34 (2H, d), 7.30 (1H, dd), 7.28-7.24 (4H, m), 4.62 (1H, d), 4.12 (1H,d), 3.61-3.53 (1H, m), 3.08-3.00 (1H, m), 2.91 (1H, d), 2.80 (1H, d),2.22 (3H, s), 1.94-7.75 (9H, m), 1.73-1.66 (3H, m), 1.43-1.20 (3H, m),0.67 (3H, dd). MS: [M+H]⁺=618.

Example 131:(3S)-3-(4-chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[1-(4-fluoro-1-methylpiperidin-4-yl)-1-hydroxypropyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]propanoicacid

(*Single Isomer Separated and Isolated)

Step 1 and 2: Starting from(−)-5-(1-(1-(tert-butoxycarbonyl)-4-fluoropiperidin-4-yl)-1-hydroxypropyl)-2-(4-chlorobenzoyl)-3-fluorobenzoicacid (Preparation 57), Steps 1 and 2 were performed using methodssimilar to those described in Example 105. MS: [M+H]⁺=661.1.

Step 3: ethyl(3S)-3-(4-chlorophenyl)-3-(1-(4-chlorophenyl)-7-fluoro-5-(1-(4-fluoro-1-methylpiperidin-4-yl)-1-hydroxypropyl)-1-methoxy-3-oxoisoindolin-2-yl)propanoate

Step 3 was performed using procedures similar to those described inExample 81, Step 5. The desired diastereoisomer was isolated usingchiral SFC as the fastest eluting isomer. MS: [M+H]⁺=675.1.

Step 4:(3S)-3-(4-chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[1-(4-fluoro-1-methylpiperidin-4-yl)-1-hydroxypropyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]propanoicacid

Step 4 was performed using methods similar those described inPreparation 52, Step 3 to give the title compound which precipitated andwas collected by filtration during the work up. ¹H NMR (400 MHz, DMSO)7.70 (1H, s), 7.42 (1H, d), 7.16 (2H, d), 7.09 (3H, d), 7.05 (1H, s),6.98 (2H, d), 5.53 (1H, s), 4.63 (1H, dd), 3.48 (1H, dd), 3.18 (1H, dd),3.08 (3H, s), 2.70-2.67 (1H, m), 2.13 (3H, s), 2.05-1.99 (1H, m),1.95-1.80 (5H, m), 1.78-1.69 (1H, m), 1.11-1.05 (1H, m), 0.55 (3H, t),OH and COOH not observed. MS: [M+H]⁺=647.3.

Example 132: tert-butyl2-{4-[(1S)-1-[(1R)-1-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-7-fluoro-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-5-yl]-1-hydroxypropyl]piperidin-1-yl}acetateExample 133: tert-butyl2-{4-[(1R)-1-[(1R)-1-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-7-fluoro-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-5-yl]-1-hydroxypropyl]piperidin-1-yl}acetate

(*Both Isomers Separated and Isolated)

Steps 1-2. Starting from5-(1-(tert-butoxycarbonyl)piperidine-4-carbonyl)-2-(4-chlorobenzoyl)-3-fluorobenzoicacid (Examples 80 and 81, step 2), steps 1-2 were performed usingmethods similar to those described in Example 73, Steps 3 and 4respectively, except T₃P was used instead of HATU in Steps 1 and MeOHinstead of 1-(hydroxymethyl)cyclopropane-1-carboxamide in Step 2 to give3-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-4-fluoro-3-methoxy-6-(piperidine-4-carbonyl)-2,3-dihydro-1H-isoindol-1-one.MS [M+H]⁺=527

Step 3: tert-butyl2-{4-[1-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-7-fluoro-1-methoxy-3-oxo-2,3-dihydro-1H-isoindole-5-carbonyl]piperidin-1-yl}acetate

To the reaction flask containing3-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-4-fluoro-3-methoxy-6-(piperidine-4-carbonyl)-2,3-dihydro-1H-isoindol-1-one(1.729 g, 3.28 mmol), K₂CO₃ (1.80 g, 13.0 mmol) and DMF (30 mL) wasadded tert-butyl bromoacetate (0.53 mL, 3.57 mmol). The reaction wasstirred at room temperature for 90 minutes at which time LCMS analysisshowed complete consumption of starting material. Solvent was thenremoved and the residue was taken up in EtOAc (10 mL) and sat. NaHCO₃.The aqueous layer was further extracted with EtOAc (3×50 mL). Thecombined organics were dried over anhydrous Na₂SO₄, filtered, andconcentrated to an oily residue. This material was then purified viaSiO₂ (petroleum ether:EtOAc) to yield 1.505 g (72%) of the racemicproduct. The racemic material was then subjected to chiral preparatoryseparation to yield the enantiomers as white solids.

Fast enantiomer: ¹H NMR (400 MHz, CDCl₃): 8.22 (1H, d), 7.75 (1H, dd),7.28 (5H, d), 7.26-7.18 (4H, m), 4.66 (1H, d), 4.07 (1H, d), 3.31-3.20(1H, m), 3.19 (2H, s), 3.04 (2H, d), 2.77 (3H, s), 2.50-2.34 (2H, m),1.99-1.84 (4H, m), 1.49 (9H, s). MS [M+NH₄]⁺=641.

Slow enantiomer: ¹H NMR (400 MHz, CDCl₃): 8.22 (1H, s), 7.75 (1H, d),7.28 (5H, s), 7.26-7.17 (4H, m), 4.66 (1H, d), 4.07 (1H, d), 3.31-3.21(1H, m), 3.19 (2H, s), 3.04 (2H, d), 2.77 (3H, s), 2.50-2.34 (2H, m),2.00-1.84 (4H, m), 1.50 (9H, s). MS [M+NH₄]⁺=641.

Step 4: Taking the slow-eluting isomer from Step 3, Step 4 was performedusing a method similar to that described in Preparation 52, Step 1.Purification by preparative chiral HPLC gave the title compounds.

Example 132—fast diastereomer: ¹H NMR (400 MHz, CDCl₃): 7.64 (1H, s),7.32-7.15 (9H, m), 4.61 (1H, d), 4.05 (1H, d), 3.05 (2H, s), 3.01 (1H,d), 2.89 (1H, d), 2.72 (3H, s), 2.16-1.96 (2H, m), 1.91 (2H, q), 1.82(1H, d), 1.74 (1H, s), 1.71-1.54 (2H, m), 1.44 (10H, s), 1.41-1.31 (1H,m), 0.68 (3H, t). MS [M+H]⁺=671.

Example 133—slow diastereomer: 1H NMR (400 MHz, CDCl₃): 7.68 (1H, s),7.33-7.17 (9H, m), 4.64 (1H, d), 4.06 (1H, d), 3.07 (2H, s), 3.04 (1H,d), 2.90 (1H, d), 2.75 (3H, s), 2.19-2.02 (2H, m), 2.02-1.89 (2H, m),1.89-1.77 (2H, m), 1.77-1.59 (2H, m), 1.59-1.45 (9H, m), 1.45-1.36 (2H,m), 0.70 (3H, t). MS [M+H]⁺=671.

Example 134:2-{4-[(1S)-1-[(1R)-1-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-7-fluoro-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-5-yl]-1-hydroxypropyl]piperidin-1-yl}aceticacid Example 135:2-{4-[(1R)-1-[(1R)-1-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-7-fluoro-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-5-yl]-1-hydroxypropyl]piperidin-1-yl}aceticacid

(*Prepared and Isolated as a Single Isomers)

Examples 134: and 135 were prepared from Examples 132 and 133respectively by using procedures similar to those described in Example121, Step 2.

Example 134: ¹H NMR (400 MHz, DMSO-d₆): 7.68 (1H, s), 7.43-7.32 (3H, m),7.32-7.21 (4H, m), 7.17 (2H, d), 4.93 (1H, s), 4.45 (1H, d), 4.14 (1H,d), 3.12 (1H, d), 3.00 (1H, d), 2.92 (2H, s), 2.73 (3H, s), 2.33-2.14(3H, m), 1.86 (2H, q), 1.82-1.67 (2H, m), 1.42-1.23 (2H, m), 1.16 (1H,d), 0.58 (3H, t). MS [M+H]⁺=615.

Example 135 1H NMR (400 MHz, DMSO-d6): 7.69 (1H, s), 7.39 (1H, d), 7.34(2H, d), 7.31-7.21 (4H, m), 7.18 (2H, d), 5.15-4.87 (1H, m), 4.46 (1H,d), 4.13 (1H, d), 3.19 (1H, d), 3.03 (3H, s), 2.73 (3H, s), 2.45-2.26(3H, m), 1.95-1.69 (4H, m), 1.47-1.31 (2H, m), 1.16 (1H, d), 0.59 (3H,t). MS [M−H]⁻=613.

Example 136: Methyl3-{4-[(1S)-1-[(1R)-1-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-7-fluoro-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-5-yl]-1-hydroxypropyl]piperidin-1-yl}propanoate

Starting from(S)-5-(1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1-hydroxypropyl)-2-(4-chlorobenzoyl)-3-fluorobenzoicacid (Preparation 60) and 4-chlorobenzylamine, the title compound wasprepared using methods similar to those described for Example 87 (Steps1-3), except that methyl methacrylate/DBU were used instead of NaBH₃CNin step 3. ¹H NMR (400 MHz, CDCl₃): 7.63 (1H, d), 7.31-7.15 (9H, m),4.61 (1H, d), 4.05 (1H, d), 3.66 (3H, s), 2.96 (1H, d), 2.84 (1H, d),2.72 (3H, s), 2.69-2.56 (2H, m), 2.47 (2H, t), 2.07-1.79 (5H, m),1.79-1.55 (3H, m), 1.40-1.28 (2H, m), 0.67 (3H, t). MS [M+H]⁺=643.

Example 137:3-{4-[(1S)-1-[(1R)-1-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-7-fluoro-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-5-yl]-1-hydroxypropyl]piperidin-1-yl}propanoicacid

Starting from Example 136, the title compound was prepared using aprocedure similar to that described in Preparation 52 (Step 3). ¹H NMR(400 MHz, DMSO): 7.69 (1H, s), 7.40 (1H, d), 7.35 (2H, d), 7.31-7.21(3H, m), 7.18 (2H, d), 4.89 (1H, s), 4.46 (1H, d), 4.13 (1H, d), 3.01(1H, d), 2.87 (1H, d), 2.74 (3H, s), 2.58-2.52 (3H, m), 2.36-2.25 (2H,m), 2.06-1.73 (5H, m), 1.71 (1H, d), 1.35-1.18 (2H, m), 1.09 (1H, d),0.57 (3H, t). MS [M−H]⁻=627.

Biological Assays

MDM2-p53 Interaction Using a 96-Well Plate Binding Assay (ELISA)

The ELISA assay was performed in streptavidin coated plates which werepreincubated with 200 μl per well of 1 μg ml⁻¹ biotinylated IP3 peptide.The plates were ready to use for MDM2 binding after washing the platewith PBS.

Compounds and control solutions in DMSO aliquoted in 96-well plates werepre-incubated in a final 2.5-5% (v/v) DMSO concentration at roomtemperature (for example 20° C.) for 20 min with 190 μl aliquots ofoptimized concentrations of in vitro translated MDM2, before transfer ofthe MDM2-compound mixture to the b-IP3 streptavidin plates, andincubation at 4° C. for 90 min. After washing three times with PBS toremove unbound MDM2, each well was incubated at 20° C. for 1 hour with aTBS-Tween (50 mM Tris pH7.5; 150 mM NaCl; 0.05% Tween 20 nonionicdetergent) buffered solution of primary mouse monoclonal anti-MDM2antibody (Ab-5, Calbiochem, used at a 1/10000 or 1/200 dilutiondepending on the antibody stock solution used), then washed three timeswith TBS-Tween before incubation for 45 mins at 20° C. with a TBS-Tweenbuffered solution of a goat-anti-mouse horseradish peroxidase (HRP)conjugated secondary antibody (used at 1/20000 or 1/2000 depending onthe antibody stock solution). The unbound secondary antibody was removedby washing three times with TBS-Tween. The bound HRP activity wasmeasured by enhanced chemiluminescence (ECL™, Amersham Biosciences)using the oxidation of the diacylhydrazide substrate, luminol, togenerate a quantifiable light signal. The percentage of MDM2 inhibitionat a given concentration is calculated as the [1−(RLU detected in thecompound treated sample—RLU negative DMSO control)÷(RLU of DMSO positiveand negative controls)]×100 or as the (RLU detected in the compoundtreated sample÷RLU of DMSO controls)×100. The IC₅₀ was calculated usinga plot of % MDM2 inhibition vs concentration and is the average of twoor three independent experiments.

Western Blot Analysis

SJSA cells were treated for 6 hours with 5, 10 and 20 μM of compounds in0.5% DMSO. The cells together with 0.5% DMSO only controls were washedwith ice-cold phosphate buffered saline (PBS) and protein extractsprepared by lysing the cells in SDS buffer (62.5 mM Tris pH 6.8; 2%sodium dodecyl sulphate (SDS); 10% glycerol) with sonication for 2×5seconds (Soniprep 150ME) to break down high molecular weight DNA andreduce the viscosity of the samples. The protein concentration of thesamples was estimated using the Pierce BCA assay system (Pierce,Rockford, Ill.) and 50 μg aliquots of protein analysed using standardSDS-polyacrylamide gel electrophoresis (SDS-PAGE) and Westernimmunoblotting procedures. 3-mercaptoethanol (5%) and bromophenol blue(0.05%) were added and the samples, which were then boiled for 5minutes, followed by brief centrifugation, before loading onto apre-cast 4-20% gradient Tris-Glycine buffered SDS-polyacrylamide gel(Invitrogen). Molecular weight standards (SeeBlue™, Invitrogen) wereincluded on every gel and electrophoresis was carried out in a Novex XLtank (Invitrogen) at 180 volts for 90 minutes. The separated proteinswere transferred electrophoretically overnight from the gel onto aHybond C nitrocellulose membrane (Amersham) using a BioRadelectrophoresis tank and 25 mM Tris, 190 mM glycine and 20% methanoltransfer buffer at 30 volts or two hours at 70 volts. Primary antibodiesused for immunodetection of the transferred proteins were: mousemonoclonal NCL-p53DO-7 (Novocastra) at 1:1000; MDM2(Ab-1, clone IF2)(Oncogene) at 1:500; WAF1 (Ab-1, clone 4D10) (Oncogene) at 1:100; Actin(AC40) (Sigma) at 1:1000. The secondary antibody used was peroxidaseconjugated, affinity purified, goat anti-mouse (Dako) at 1:1000. Proteindetection and visualisation was performed by enhanced chemiluminescence(ECL™, Amersham) with light detection by exposure to blue-sensitiveautoradiography film (Super RX, Fuji).

Protocol A: SJSA-1 and SN40R2 Assays

The MDM2 amplified cell lines tested were an isogenic matched pair ofp53 wild-type and mutated osteosarcoma (SJSA-1 and SN40R2,respectively). All cell cultures were grown in RPMI 1640 medium (Gibco,Paisley, UK) supplemented with 10% fetal calf serum and routinely testedand confirmed negative for mycoplasma infection. The growth of cells andits inhibition was measured using the sulphorhodamine B (SRB) method aspreviously outlined. 100 μl of 3×10⁴/ml and 2×10⁴/ml SJSA-1 and SN40R2cells, respectively, were seeded into 96-well tissue culture plates andincubated at 37° C. in a 5% CO₂ humidified incubator for 24 hrs, afterwhich the medium was replaced with 100 μl of test medium containing arange of MDM2-p53 antagonist concentrations and incubated for a further72 hrs to allow cell growth before adding 25 μL of 50% trichloroaceticacid (TCA) to fix the cells for 1 h at 4° C. The TCA was washed off withdistilled water and 100 μL of SRB dye (0.4% w/v in 1% acetic acid)(Sigma-Aldrich, Poole, Dorset) added to each well of the plate.Following incubation with the SRB dye at room temperature for 30 min,the plates were washed with 1% acetic acid and left to dry. The SRBstained protein, which is a measure of the number of cells in a well,was then resuspended in 100 μL of 10 mM Tris-HCl (pH 10.5) and theabsorbance at λ=570 nm measured in each well using a FluoStar OmegaPlate reader. The GI₅₀ was calculated by non-linear regression analysisof the data using Prism v4.0 statistical software.

Protocol B: SJSA-1 and SN40R2 Assays

The CellTiter-Glo® Luminescent Cell Viability Assay is a homogeneousmethod to determine the number of viable cells in culture based onquantitation of the ATP present, which signals the presence ofmetabolically active cells. Both SJSA-1 and SN40R2 were grown in RPMI1640 (Life Technologies #61870) supplemented with 10% FBS (PAA #A15-204)and 10 U/ml penicillin/streptomycin. 2000 cells in 75 μl were seeded ineach well of a 96 well plate and left at 37° C. in a 5% CO₂ humidifiedincubator for 24 hrs. A range of MDM2-p53 antagonist concentrations inDMSO was then added to the cells to a final DMSO concentration of 0.3%,and incubated for a further 72 hrs to allow cell growth. 100 μl of CTGreagent (Promega #G7573) was added to all wells and luminescence wasmeasured on the topcount. The EC₅₀ values were determined from asigmoidal 4 parameter curve fit using XLfit in conjunction with ActivityBase (IDBS; Guildford, Surrey, UK).

Anti-Proliferative Activity

Inhibition of cell growth is measured using the Alamar Blue assay(Nociari, M. M, Shalev, A., Benias, P., Russo, C. Journal ofImmunological Methods 1998, 213, 157-167). The method is based on theability of viable cells to reduce resazurin to its fluorescent productresorufin. For each proliferation assay cells are plated onto 96 wellplates and allowed to recover for 16 hours prior to the addition ofinhibitor compounds (in 0.1% DMSO v/v) for a further 72 hours. At theend of the incubation period 10% (v/v) Alamar Blue is added andincubated for a further 6 hours prior to determination of fluorescentproduct at 535 nM ex/590 nM em. The anti-proliferative activities ofcompounds of the invention can be determined by measuring the ability ofthe compounds to inhibit growth in cancer cell lines for example asavailable from DSMZ, ECACC or ATCC.

Results

TABLE 1 biological data obtained from assays as described herein SJSA-1IC50 SJSA1 IC50 (μM) (μM) SN40R2 SN40R2 IC50 Patent MDM2 IC50 (Protocol(Protocol IC50 (μM) (μM) Example (μM) A) B) (Protocol A) (Protocol B) 10.012 0.49 0.55 18 10% at 10 2 0.0046 0.33 0.46 17 22% at 10 3 0.093 40.043 5 0.14 6 0.12 7 0.0066 8 0.0047 0.33 18 9 0.011 10 0.0037 0.14 7.511 0.033 12 0.0058 0.51 0.69 5.9 13 0.12 4.6 5.9 14 0.0050 0.83 0.49 10%at 30  9% at 10 15 0.019 16 0.14 2.1 13 17 0.063 0.95 8.1 18 0.045 0.8018 19 0.022 0.62 2.0 13 13 20 0.011 0.33 11 21 0.0078 0.23 0.39 15 51%at 10 22 0.0052 0.21 18 24 0.0075 0.37 0.63 21 19% at 10 25 0.0072 0.711.1 25 14% at 10 26 0.032 1.7 17 27 0.065 2.1 29% at 30 28 0.026 0.9326% at 30 29 0.11 1.4 17 30 0.086 2.4 27 31 0.038 1.2 18 32 0.87 15 330.0019 9.1  7% at 30 34 0.0046 0.093 9.9 35 0.0018 0.16 0.69 23 13 360.0019 0.078 17 37 0.041 1.2 13 38 0.026 0.67 17 39 0.068 2.0 18 400.063 1.5 17 41 0.0016 0.14 13 42  34%@0.00030 0.011 0.03 12 10 4347%@0.0010 0.57 12 44 0.0058 0.83 6.8 45 0.23 46 10.78 47 0.43 48 0.00730.46 0.97 17 24% at 10 49 0.082 1.6 18 50 0.00080 0.079 0.032 17 22% at10 51 0.13 52 0.15 1.8 53 0.12 1.9 54 0.15 55 1.7 11 56 0.12 57 0.0611.4 16 58 0.018 0.59 15 59 0.0041 0.25 19 60 0.014 61 0.016 0.69 44% at30 62 0.0023 0.055 55% at 30 63 71%@0.0010 0.096 19% at 10 64 0.0021 650.0018 0.26 66 0.0030 67 60%@0.0010 0.53 9.4 68 0.0070 1.8 13 69 0.000700.081 0.16 15 6.6 70 0.0057 0.68 4.9 71 0.0020 0.66 0.7 44  3% at 10 720.0015 0.14 0.17 16 45% at 10 73 0.012 3.6 39% at 30 74 0.00050 0.28 1.028 13 75 73%@0.0010 0.12 0.35 22 12 76 0.0095 1.0 13 77  61%@0.000300.46 3.7 78 0.0046 0.41 1.4 5.9 4.2 79 0.0022 8.1 10% at 30 8073%@0.0010 0.83 13 81 0.0026 82 0.0025 0.21 51% at 30 83 0.0010 0.53 1184  39%@0.00030 0.065 18 85 0.00049 0.049 13 86 56%@0.10  87 82%@0.003037% at 10  1% at 10 88 0.00079 0.15 0.23 39 11% at 10 89 0.012 3.6  3%at 10 90 39%@0.030  97% at 10  6% at 10 91 78%@0.0010 0.080 0.059 26 13%at 10 92 76%@0.0010 0.080 0.084 36 12% at 10 93 49%@0.030  3.3 12% at 1094 64%@0.10  95 87%@0.0010 0.036 0.022 16 21% at 10 96 0.00064 0.0710.075 19 17% at 10 97 45%@0.10  98 0.0008 0.081 0.13 33 11% at 10 990.012 3.2  4% at 10 100 0.0063 1.7  7% at 10 101  55%@0.00030 0.0260.026 18 11% at 3  102 0.017 1.4 26% at 10 103 55%@0.030  0.8 18% at 10104 70%@0.10  42% at 10  5% at 10 105 92%@0.0010 0.022 0.05 33 20% at 10106 57%@0.030  3.2  8% at 10 107 78%@0.0010 0.021 0.038 24 18% at 10 1080.0061 27% at 10 29% at 10 109 92%@0.0010 0.012 0.02 26 75% at 10 11076%@0.0010 0.026 0.013 17 30% at 10 111 61%@0.0010 0.024 0.037 9 51% at10 113 57%@0.0010 0.02 10% at 10 114 81%@0.0010 0.029 0.063 20 15% at 10115 73%@0.0010 0.22  2% at 10 116 88%@0.0010 0.08 0.14 44 12% at 10 11745% at 0.03 30% at 10 19% at 10 118 87%@0.0010 0.36  8% at 10 11954%@0.0010 0.06 0.2 39  7% at 10 120 76%@0.0010 0.063 0.095 40% at 50 4% at 10 121 93%@0.0010 0.015 0.015 26 18% at 10 122 88%@0.0010 0.02420% at 10 123 42%@0.030  107% at 10  16% at 10 124 80%@0.0010 0.0230.027 23 55% at 10 125 18%@0.10  126 0.0019 0.6 0.61 30  7% at 10 1270.0045 1.4 14% at 10 128 39%@0.10  129 90%@0.0010 0.047 0.048 6 112% at10  130 98%@0.0010 0.23 87% at 10 131 89%@0.0010 0.044 0.093 22 −3% at10  132 43%@0.030  0.75 34% at 10 133 6%@0.10  37% at 10 89% at 10 1340.0011 0.78  2% at 10 135 40%@0.10  20% at 10  7% at 10 136 0.0013 0.05686% at 10 137 0.00057 0.15 12% at 10

Where more than one data point has been obtained, the table above showsan average (e.g. geometric or arithmetic mean) of these data points.

It is of course to be understood that the invention is not intended tobe restricted to the details of the above embodiments which aredescribed by way of example only.

Combination Protocol for Cell Proliferation

The effect of a compound of formula (I) (Compound 1) in combination withan anticancer agent (Compound II) can be assessed using the followingtechnique. Cells from human cells lines (e.g. SJSA-1) were seeded onto96-well tissue culture plates at a concentration of 2.5×10³, 6.0×10³, or4.0×10³ cells/well respectively. Cells were allowed to recover for 24-48hours prior to addition of compound(s) or vehicle control (0.35-0.5%DMSO) as follows:

Compounds were added concurrent for 72-96 hours. Following a total of72-96 hours compound incubation, cells were fixed with ice-cold 10%(w/v) trichloroacetic acid for 1 hour on ice and then washed four timeswith dH₂O using a plate washer (Labsystems Wellwash Ascent) andair-dried. Cells were then stained with 0.4% (w/v) Sulforhodamine B(Sigma) in 1% acetic acid for 20 min at room temperature and then washedfour times with 1% (v/v) acetic acid and air-dried before the additionof 10 mM Tris buffer to solubilise the dye. Colourmetric product wasquantified by reading at Abs490 nm or Abs570 nm on a Wallac Victor²plate reader (1420 multilabel counter, Perkin Elmer Life Sciences). TheIC₅₀ for Compound II in the presence of varying doses of Compound I wasdetermined. Synergy was determined when the IC₅₀ shifted down in thepresence of sub-effective doses of Compound I. Additivity was determinedwhen the response to Compound II and Compound I together resulted in aneffect equivalent to the sum of the two compounds individually.Antagonistic effects were defined as those causing the IC₅₀ to shiftupwards, i.e. those where the response to the two compounds was lessthan the sum of the effect of the two compounds individually.

Pharmaceutical Formulations Examples

(i) Tablet Formulation

A tablet composition containing a compound of the formula (I) isprepared by mixing an appropriate amount of the compound (for example50-250 mg) with an appropriate diluent, disintegrant, compression agentand/or glidant. One possible tablet comprises 50 mg of the compound with197 mg of lactose (BP) as diluent, and 3 mg magnesium stearate as alubricant and compressing to form a tablet in known manner. Thecompressed tablet may be optionally film coated.

(ii) Capsule Formulation

A capsule formulation is prepared by mixing 100-250 mg of a compound ofthe formula (I) with an equivalent amount of lactose and filling theresulting mixture into standard hard gelatin capsules. An appropriatedisintegrant and/or glidant can be included in appropriate amounts asrequired.

(iii) Injectable Formulation I

A parenteral composition for administration by injection can be preparedby dissolving a compound of the formula (I) (e.g. in a salt form) inwater containing 10% propylene glycol to give a concentration of activecompound of 1.5% by weight. The solution is then made isotonic,sterilised by filtration or by terminal sterilisation, filled into anampoule or vial or pre-filled syringe, and sealed.

(iv) Injectable Formulation II

A parenteral composition for injection is prepared by dissolving inwater a compound of the formula (I) (e.g. in salt form) (2 mg/ml) andmannitol (50 mg/ml), sterile filtering the solution or by terminalsterilisation, and filling into sealable 1 ml vials or ampoules orpre-filled syringe.

(v) Injectable Formulation III

A formulation for i.v. delivery by injection or infusion can be preparedby dissolving the compound of formula (I) (e.g. in a salt form) in waterat 20 mg/ml and then adjusted for isotonicity. The vial is then sealedand sterilised by autoclaving or filled into an ampoule or vial orpre-filled syringe, sterilised by filtration and sealed.

(vi) Injectable Formulation IV

A formulation for i.v. delivery by injection or infusion can be preparedby dissolving the compound of formula (I) (e.g. in a salt form) in watercontaining a buffer (e.g. 0.2 M acetate pH 4.6) at 20 mg/ml. The vial,ampoule or pre-filled syringe is then sealed and sterilised byautoclaving or sterilized by filtration and sealed.

(vii) Subcutaneous or Intramuscular Injection Formulation

A composition for sub-cutaneous or intramuscular administration isprepared by mixing a compound of the formula (I) with pharmaceuticalgrade corn oil to give a concentration of 5-50 mg/ml. The composition issterilised and filled into a suitable container.

(viii) Lyophilised Formulation I

Aliquots of formulated compound of formula (I) are put into 50 ml vialsand lyophilized. During lyophilisation, the compositions are frozenusing a one-step freezing protocol at (−45° C.). The temperature israised to −10° C. for annealing, then lowered to freezing at −45° C.,followed by primary drying at +25° C. for approximately 3400 minutes,followed by a secondary drying with increased steps if temperature to50° C. The pressure during primary and secondary drying is set at 80millitor.

(ix) Lyophilised Formulation II

Aliquots of formulated compound of formula (I) or a salt thereof asdefined herein are put into 50 mL vials and lyophilized. Duringlyophilisation, the compositions are frozen using a one-step freezingprotocol at (−45° C.). The temperature is raised to −10° C. forannealing, then lowered to freezing at −45° C., followed by primarydrying at +25° C. for approximately 3400 minutes, followed by asecondary drying with increased steps if temperature to 50° C. Thepressure during primary and secondary drying is set at 80 millitor.

(x) Lyophilised Formulation for Use in i.v. Administration III

An aqueous buffered solution is prepared by dissolving a compound offormula I in a buffer. The buffered solution is filled, with filtrationto remove particulate matter, into a container (such as a Type 1 glassvial) which is then partially sealed (e.g. by means of a Fluorotecstopper). If the compound and formulation are sufficiently stable, theformulation is sterilised by autoclaving at 121° C. for a suitableperiod of time. If the formulation is not stable to autoclaving, it canbe sterilised using a suitable filter and filled under sterileconditions into sterile vials. The solution is freeze dried using asuitable cycle. On completion of the freeze drying cycle the vials areback filled with nitrogen to atmospheric pressure, stoppered and secured(e.g. with an aluminium crimp). For intravenous administration, thefreeze dried solid can be reconstituted with a pharmaceuticallyacceptable diluent, such as 0.9% saline or 5% dextrose. The solution canbe dosed as is, or can be diluted further into an infusion bag(containing a pharmaceutically acceptable diluent, such as 0.9% salineor 5% dextrose), before administration.

(xii) Powder in a Bottle

A composition for oral administration is prepared by filling a bottle orvial with a compound of the formula (I). The composition is thenreconstituted with a suitable diluent for example water, fruit juice, orcommercially available vehicle such as OraSweet or Syrspend. Thereconstituted solution may be dispensed into dosing cups or oralsyringes for administration.

1. A compound of formula (I):

or a tautomer or a solvate or a pharmaceutically acceptable saltthereof, wherein: R¹ is independently selected from hydroxy, halogen,nitro, nitrile, C₁₋₄alkyl, haloC₁₋₄alkyl, hydroxyC₁₋₄alkyl, C₂₋₆alkenyl,C₁₋₄alkoxy, haloC₁₋₄alkoxy, C₂₋₄alkynyl,—O_(0,1)—(CR^(x)R^(y))_(v)—CO₂H, —(CR^(x)R^(y))_(v)—CO₂C₁₋₄alkyl,—(CR^(x)R^(y))_(v)—CON(C₁₋₄alkyl)₂, —P(═O)(R^(x))₂, —S(O)_(d)—R^(x),—S(O)_(d)-heterocyclic group with 3 to 6 ring members and—S(O)_(d)—N(R⁸)₂; R² is selected from hydrogen, C₁₋₄ alkyl, C₂₋₆alkenyl,hydroxyC₁₋₄alkyl, —(CR^(x)R^(y))_(u)—CO₂H,—(CR^(x)R^(y))_(u)—CO₂C₁₋₄alkyl, and —(CR^(x)R^(y))_(u)—CONR^(x)R^(y); sis selected from 0 and 1; R³ is hydrogen or-(A)_(t)-(CR^(x)R^(y))_(q)—X; t is selected from 0 and 1; q is selectedfrom 0, 1 and 2; wherein when R³ is -(A)_(t)-(CR^(x)R^(y))_(q)—X then(i) at least one of s, t and q is other than 0 and (ii) when t is 0 thens is 1 and q is other than 0; A is a C₃₋₆cycloalkyl group or aheterocyclic group with 3 to 6 ring members, wherein the heterocyclicgroup comprises one or more heteroatoms selected from N, O, S andoxidised forms thereof; X is selected from hydrogen, halogen, —CN, —OR⁹,—(CH₂)_(v)—CO₂H, —(CH₂)_(v)—CO₂C₁₋₄alkyl, —S(O)_(d)—R^(x),—C(═O)—C₁₋₄alkyl, —S(O)_(d)—N(H)_(e)(C₁₋₄alkyl)_(2-e), —NR^(x)R^(y),—NHSO₂R^(x), —NR^(x)COR^(y), and —C(═O)NR^(x)R^(y); R⁴ and R⁵ areindependently selected from halogen, nitrile, C₁₋₄ alkyl, haloC₁₋₄alkyl,C₁₋₄alkoxy and haloC₁₋₄alkoxy; R⁶ and R⁷ are independently selected fromhydrogen, C₁₋₆alkyl, haloC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, hydroxy,hydroxyC₁₋₆alkyl, —COOC₁₋₆alkyl, —(CH₂)_(j)—O—C₁₋₆alkyl,—(CH₂)_(j)—O-(hydroxyC₁₋₆alkyl), —C₁₋₆alkyl-NR^(x)R^(y),—(CR^(x)R^(y))_(p)—CONR^(x)R^(y), —(CR^(x)R^(y))_(p)—NR^(x)COR^(y),—(CR^(x)R^(y))_(p)—O—CH₂—CONR^(x)R^(y), heterocyclic group with 3 to 7ring members, —CH₂-heterocyclic group with 3 to 7 ring members,—CH₂—O-heterocyclic group with 3 to 7 ring members, —CH₂—NH-heterocyclicgroup with 3 to 7 ring members, —CH₂—N(C₁₋₆alkyl)-heterocyclic groupwith 3 to 7 ring members, —C(═O)NH-heterocyclic group with 3 to 7 ringmembers, C₃₋₈cycloalkyl, —CH₂—C₃₋₈cycloalkyl, —CH₂—O—C₃₋₈cycloalkyl, andC₃₋₈cycloalkenyl, wherein said cycloalkyl, cycloalkenyl or heterocyclicgroups may be optionally substituted by one or more R^(z) groups, andwherein in each instance the heterocyclic group comprises one or moreheteroatoms selected from N, O, S and oxidised forms thereof; or the R⁶and R⁷ groups, together with the carbon atom to which they are attached,can join to form a C₃₋₆cycloalkyl or heterocyclyl group with 3 to 6 ringmembers, wherein the heterocyclic group comprises one or moreheteroatoms selected from N, O, S and oxidised forms thereof, andwherein said C₃₋₆cycloalkyl and heterocyclyl groups may be optionallysubstituted by one or more R^(z) groups; R⁸ and R⁹ are independentlyselected from hydrogen, C₁₋₆alkyl, haloC₁₋₆alkyl, hydroxyC₁₋₆alkyl,—(CH₂)_(k)—O—C₁₋₆alkyl, —(CH₂)_(k)—O-(hydroxyC₁₋₆alkyl),hydroxyC₁₋₆alkoxy, —(CH₂)_(k)—CO₂C₁₋₆alkyl, —(CH₂)_(k)—CO₂H, —C₁₋₆alkyl-N(H)_(e)(C₁₋₄alkyl)_(2-e), —(CH₂)_(j)—C₃₋₈cycloalkyl and—(CH₂)_(j)—C₃₋₈cycloalkenyl; R^(x) and R^(y) are independently selectedfrom hydrogen, halogen, nitro, nitrile, C₁₋₆alkyl, haloC₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, hydroxy, hydroxyC₁₋₆alkyl, C₁₋₆alkoxy,—(CH₂)_(k)—O—C₁₋₆alkyl, hydroxyC₁₋₆alkoxy, —COOC₁₋₆alkyl,—N(H)_(e)(C₁₋₄alkyl)_(2-e), —C₁₋₆alkyl-N(H)_(e)(C₁₋₄alkyl)_(2-e),—(CH₂)_(k)—C(═O)N(H)_(e)(C₁₋₄alkyl)_(2-e), C₃₋₈cycloalkyl andC₃₋₈cycloalkenyl; or the R^(x) and R^(y) groups, together with thecarbon or nitrogen atom to which they are attached, can join to form aC₃₋₆cycloalkyl or saturated heterocyclyl group with 3 to 6 ring memberswhich may be optionally fused to an aromatic heterocyclyl group of 3 to5 ring members; or when on a carbon atom the R^(x) and R^(y) groups canjoin together to form a ═CH₂ group; R^(z) is independently selected fromhalogen, nitro, nitrile, C₁₋₆alkyl, haloC₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, ═O, hydroxy, hydroxyC₁₋₆alkyl, C₁₋₆alkoxy,—(CH₂)_(k)—O—C₁₋₆alkyl, hydroxyC₁₋₆alkoxy, —C(═O)C₁₋₆alkyl,—C(═O)C₁₋₆alkyl-OH, —C(═O)C₁₋₆alkyl-N(H)_(e)(C₁₋₄alkyl)_(2-e),—C(═O)N(H)_(e)(C₁₋₄alkyl)_(2-e), —(CH₂)_(r)—CO₂C₁₋₆alkyl,—(CH₂)_(r)—CO₂H, —N(H)_(e)(C₁₋₄alkyl)_(2-e),—C₁₋₆alkyl-N(H)_(e)(C₁₋₄alkyl)_(2-e), heterocyclyl group with 3 to 6ring members, heterocyclyl group with 3 to 6 ring members substituted by—C(═O)C₁₋₄alkyl, heterocyclyl group with 3 to 6 ring members substitutedby —C(═O)OC₁₋₄alkyl, heterocyclyl group with 3 to 6 ring memberssubstituted by —C(═O)N(H)_(e)(C₁₋₄alkyl)_(2-e), —C(═O)heterocyclyl groupwith 3 to 6 ring members, C₃₋₈cycloalkyl and C₃₋₈cycloalkenyl, whereinif R⁷ is pyridine then R^(z) is other then —NH₂; a, j, d, e, n, r and pare independently selected from 0, 1 and 2; k and m are independentlyselected from 1 and 2; u is selected from 0, 1, 2 and 3; and v and w areindependently selected from 0 and
 1. 2. A compound according to claim 1,or a tautomer or a solvate or a pharmaceutically acceptable saltthereof, wherein R¹ is: (i) halogen, hydroxy, nitrile, C₁₋₄alkyl,C₂₋₄alkynyl, or C₁₋₄alkoxy, for example wherein n is 1 and R¹ is chloroor nitrile e.g. chloro; or (ii) hydroxy, halogen, nitrile, C₁₋₄alkyl,haloC₁₋₄alkyl, hydroxyC₁₋₄alkyl, C₂₋₆alkenyl, C₁₋₄alkoxy,haloC₁₋₄alkoxy, C₂₋₄alkynyl, —(CH₂)_(v)—CO₂H,—O_(0,1)—(CR^(x)R^(y))_(v)—CO₂C₁₋₄alkyl, —(CH₂)_(v)—CON(C₁₋₄alkyl)₂,—P(═O)(R^(x))₂, —S(O)_(d)—C₁₋₆alkyl, —S(O)_(d)-heterocyclic group with 3to 6 ring members or —S(O)_(d)—N(R⁸)₂. 3-6. (canceled)
 7. A compoundaccording to claim 1, or a tautomer or a solvate or a pharmaceuticallyacceptable salt thereof, wherein R² is: (i) hydrogen, C₁₋₄ alkyl,C₂₋₆alkenyl, or hydroxyC₁₋₄alkyl; or (ii) hydrogen or—(R^(x)R^(y))_(u)—CO₂H (e.g. —COOH, —CH₂COOH, —CH₂CH₂—CO₂H,—(CH(CH₃))—CO₂H or —(C(CH₃)₂—CO₂H).
 8. (canceled)
 9. A compoundaccording to claim 1, or a tautomer or a solvate or a pharmaceuticallyacceptable salt thereof, wherein: (i) R³ is -(A)_(t)-(CR^(x)R^(y))_(q)—Xand A is either a C₃₋₆cycloalkyl group e.g. a cyclopropyl group or aheterocyclic group with 3 to 5 ring members e.g. a heterocyclic groupwith 5 ring members; or (ii) R³ is -(A)_(t)-(CR^(x)R^(y))_(q)—X and A isa heterocyclic group with 3 to 5 ring members e.g. a heterocyclic groupwith 5 ring members.
 10. (canceled)
 11. A compound according to claim 1,or a tautomer or a solvate or a pharmaceutically acceptable saltthereof, wherein s is 0 or
 1. 12. (canceled)
 13. A compound according toclaim 1, or a tautomer or a solvate or a pharmaceutically acceptablesalt thereof, wherein X is hydrogen, halogen, —CN, —OR⁹ or—C(═O)NR^(x)R^(y).
 14. A compound according to claim 1, wherein thecompound is a compound of the formula

or a tautomer or a solvate or a pharmaceutically acceptable saltthereof.
 15. A compound according to claim 1, or a tautomer or a solvateor a pharmaceutically acceptable salt thereof, wherein a is 1 and R⁴ isF and at the 4-position of the isoindolinone ring.
 16. (canceled) 17.(canceled)
 18. A compound according to claim 1, or a tautomer or asolvate or a pharmaceutically acceptable salt thereof, wherein R⁵ ischloro and m is 1 and the substituent R⁵ is at the para-position of thephenyl group.
 19. A compound according to claim 1, or a tautomer or asolvate or a pharmaceutically acceptable salt thereof, wherein: (i) R⁷is selected from a heterocyclic group with 3 to 7 ring member and a—CH₂-heterocyclic group with 3 to 7 ring members, wherein saidheterocyclic groups may be optionally substituted by one or more R^(z)groups, and wherein in each instance the heterocyclic group comprisesone or more heteroatoms selected from N, O, S and oxidised formsthereof; or (ii) R⁶ is methyl or ethyl.
 20. (canceled)
 21. A compoundaccording to claim 1, wherein the compound is a compound of formula (bb)or a tautomer or a solvate or a pharmaceutically acceptable saltthereof:


22. (canceled)
 23. A compound according to claim 1, or a tautomer,N-oxide, pharmaceutically acceptable salt or solvate thereof, whereinthe compound is selected from:(3R)-3-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-3-{[1-(hydroxymethyl)cyclopropyl]methoxy}-6-(2-hydroxypropan-2-yl)-2,3-dihydro-1H-isoindol-1-one;(3R)-3-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-4-fluoro-3-{[1-(hydroxymethyl)cyclopropyl]methoxy}-6-(2-hydroxypropan-2-yl)-2,3-dihydro-1H-isoindol-1-one;(3R)-3-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-3-(2-hydroxyethoxy)-6-(2-hydroxypropan-2-yl)-2,3-dihydro-1H-isoindol-1-one;(3R)-3-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-3-{[3-(hydroxymethyl)oxetan-3-yl]methoxy}-6-(2-hydroxypropan-2-yl)-2,3-dihydro-1H-isoindol-1-one;1-({[(1R)-1-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-5-(2-hydroxypropan-2-yl)-3-oxo-2,3-dihydro-1H-isoindol-1-yl]oxy}methyl)cyclopropane-1-carboxylicacid;(3R)-3-(4-chlorophenyl)-2-[(1S)-1-(4-chlorophenyl)ethyl]-3-(2,3-dihydroxy-2-methylpropoxy)-6-(2-hydroxypropan-2-yl)-2,3-dihydro-1H-isoindol-1-one;(3R)-3-(4-chlorophenyl)-2-[(1S)-1-(4-chlorophenyl)ethyl]-3-{[1-(hydroxymethyl)cyclopropyl]methoxy}-6-(2-hydroxypropan-2-yl)-2,3-dihydro-1H-isoindol-1-one;(3R)-3-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-6-(1,2-dihydroxypropan-2-yl)-3-{[1-(hydroxymethyl)cyclopropyl]methoxy}-2,3-dihydro-1H-isoindol-1-one;(3R)-3-(4-chlorophenyl)-2-[(1S)-1-(4-chlorophenyl)ethyl]-6-(2-hydroxy-1-methoxypropan-2-yl)-3-{[1-(hydroxymethyl)cyclopropyl]methoxy}-2,3-dihydro-1H-isoindol-1-one;(3R)-3-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-6-[1-(dimethylamino)-2-hydroxypropan-2-yl]-3-{[1-(hydroxymethyl)cyclopropyl]methoxy}-2,3-dihydro-1H-isoindol-1-one;(3S)-3-(4-chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-1-{[1-(hydroxymethyl)cyclopropyl]methoxy}-5-(2-hydroxypropan-2-yl)-3-oxo-2,3-dihydro-1H-isoindol-2-yl]propanoicacid;(3R)-3-(4-chlorophenyl)-2-[(1S)-1-(4-chlorophenyl)ethyl]-6-(1,2-dihydroxypropan-2-yl)-3-{[1-(hydroxymethyl)cyclopropyl]methoxy}-2,3-dihydro-1H-isoindol-1-one;(3R)-3-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-3-(3-hydroxy-3-methylbutoxy)-6-(2-hydroxypropan-2-yl)-2,3-dihydro-1H-isoindol-1-one;(3R)-3-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-6-(2-hydroxypropan-2-yl)-3-[(1H-pyrazol-4-yl)methoxy]-2,3-dihydro-1H-isoindol-1-one;1-({[(1R)-1-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-5-(2-hydroxypropan-2-yl)-3-oxo-2,3-dihydro-1H-isoindol-1-yl]oxy}methyl)cyclopropane-1-carbonitrile;N-{[1-({[(1R)-1-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-5-(2-hydroxypropan-2-yl)-3-oxo-2,3-dihydro-1H-isoindol-1-yl]oxy}methyl)cyclopropyl]methyl}methanesulfonamide;(3R)-3-(4-chlorophenyl)-2-[(4-ethynylphenyl)methyl]-3-{[1-(hydroxymethyl)cyclopropyl]methoxy}-6-(2-hydroxypropan-2-yl)-2,3-dihydro-1H-isoindol-1-one;(3R)-3-(4-chlorophenyl)-2-[(4-ethynylphenyl)methyl]-4-fluoro-3-{[1-(hydroxymethyl)cyclopropyl]methoxy}-6-(2-hydroxypropan-2-yl)-2,3-dihydro-1H-isoindol-1-one;(3R)-3-(4-chlorophenyl)-6-(1,2-dihydroxypropan-2-yl)-2-[(4-ethynylphenyl)methyl]-4-fluoro-3-{[1-(hydroxymethyl)cyclopropyl]methoxy}-2,3-dihydro-1H-isoindol-1-one;4-{[(1R)-1-(4-chlorophenyl)-7-fluoro-1-({1-[hydroxy(²H₂)methyl]cyclopropyl}(²H₂)methoxy)-5-(2-hydroxypropan-2-yl)-3-oxo-2,3-dihydro-1H-isoindol-2-yl]methyl}benzonitrile;4-{[(1R)-1-(4-chlorophenyl)-1-{[1-(hydroxymethyl)cyclopropyl]methoxy}-5-(2-hydroxypropan-2-yl)-3-oxo-2,3-dihydro-1H-isoindol-2-yl]methyl}benzonitrile;(3R)-3-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-6-(2-hydroxypropan-2-yl)-3-[(3-methyloxetan-3-yl)methoxy]-2,3-dihydro-1H-isoindol-1-one;4-{[(1R)-1-(4-chlorophenyl)-5-(1,2-dihydroxypropan-2-yl)-1-{[1-(hydroxymethyl)cyclopropyl]methoxy}-3-oxo-2,3-dihydro-1H-isoindol-2-yl]methyl}benzonitrile;(3R)-3-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-3-[(1-hydroxycyclopropyl)methoxy]-6-(2-hydroxypropan-2-yl)-2,3-dihydro-1H-isoindol-1-one;2-{[(1R)-1-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-5-(2-hydroxypropan-2-yl)-3-oxo-2,3-dihydro-1H-isoindol-1-yl]oxy}-N,N-dimethylacetamide;(3R)-3-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-6-(2-hydroxypropan-2-yl)-3-{[1-(methoxymethyl)cyclopropyl]methoxy}-2,3-dihydro-1H-isoindol-1-one;(3R)-3-(4-Chlorophenyl)-2-[(4-chlorophenyl)methyl]-3-{[1-(hydroxymethyl)cyclobutyl]methoxy}-6-(2-hydroxypropan-2-yl)-2,3-dihydro-1H-isoindol-1-one;5-chloro-2-{[(1R)-1-(4-chlorophenyl)-1-{[1-(hydroxymethyl)cyclopropyl]methoxy}-5-(2-hydroxypropan-2-yl)-3-oxo-2,3-dihydro-1H-isoindol-2-yl]methyl}benzoicacid;(3R)-2-{[4-chloro-2-(morpholine-4-sulfonyl)phenyl]methyl}-3-(4-chlorophenyl)-3-{[1-(hydroxymethyl)cyclopropyl]methoxy}-6-(2-hydroxypropan-2-yl)-2,3-dihydro-1H-isoindol-1-one;1-({[(1R)-2-[(4-chloro-2-methanesulfonylphenyl)methyl]-1-(4-chlorophenyl)-7-fluoro-5-(2-hydroxypropan-2-yl)-3-oxo-2,3-dihydro-1H-isoindol-1-yl]oxy}methyl)cyclopropane-1-carboxamide;(3R)-2-[(4-chloro-2-methanesulfonylphenyl)methyl]-3-(4-chlorophenyl)-3-({1-[hydroxy(²H₂)methyl]cyclopropyl}(²H₂)methoxy)-6-(2-hydroxypropan-2-yl)-2,3-dihydro-1H-isoindol-1-one;(3R)-3-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-6-(2-hydroxypropan-2-yl)-3-(oxolan-3-yloxy)-2,3-dihydro-1H-isoindol-1-one;(3R)-3-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-6-(2-hydroxypropan-2-yl)-3-[(oxolan-3-yl)methoxy]-2,3-dihydro-1H-isoindol-1-one;(3R)-2-[(4-chloro-2-methanesulfonylphenyl)methyl]-3-(4-chlorophenyl)-4-fluoro-6-[1-hydroxy-1-(oxan-4-yl)ethyl]-3-{[1-(hydroxymethyl)cyclopropyl]methoxy}-2,3-dihydro-1H-isoindol-1-one;(3R)-2-[(4-chloro-2-methanesulfonylphenyl)methyl]-3-(4-chlorophenyl)-4-fluoro-6-[2-hydroxy-1-(piperazin-1-yl)propan-2-yl]-3-{[1-(hydroxymethyl)cyclopropyl]methoxy}-2,3-dihydro-1H-isoindol-1-one;(3R)-3-(4-chlorophenyl)-2-[(1S)-1-(4-chlorophenyl)ethyl]-3-{[(3S,4R)-4-hydroxyoxolan-3-yl]oxy}-6-(2-hydroxypropan-2-yl)-2,3-dihydro-1H-isoindol-1-one;(3R)-3-(4-chlorophenyl)-2-[(1S)-1-(4-chlorophenyl)ethyl]-3-{[(3R,4S)-4-hydroxyoxolan-3-yl]oxy}-6-(2-hydroxypropan-2-yl)-2,3-dihydro-1H-isoindol-1-one;(3R)-3-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-6-(2-hydroxypropan-2-yl)-3-methoxy-2,3-dihydro-1H-isoindol-1-one;(3R)-3-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-3-({1-[hydroxy(²H₂)methyl]cyclopropyl}(²H₂)methoxy)-6-(2-hydroxypropan-2-yl)-2,3-dihydro-1H-isoindol-1-one;(3R)-3-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-6-(2-hydroxypropan-2-yl)-3-(3-hydroxypropoxy)-2,3-dihydro-1H-isoindol-1-one;(3R)-2-[(4-chloro-2-methanesulfonylphenyl)methyl]-3-(4-chlorophenyl)-4-fluoro-3-{[1-(hydroxymethyl)cyclopropyl]methoxy}-6-(2-hydroxypropan-2-yl)-2,3-dihydro-1H-isoindol-1-one;(3R)-3-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-3-(2,2-difluoro-3-hydroxypropoxy)-6-(2-hydroxypropan-2-yl)-2,3-dihydro-1H-isoindol-1-one;(3R)-3-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-3-{[2-(hydroxymethyl)cyclobutyl]methoxy}-6-(2-hydroxypropan-2-yl)-2,3-dihydro-1H-isoindol-1-one;(3R)-3-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-6-[2-hydroxy-1-oxo-1-(pyrrolidin-1-yl)propan-2-yl]-3-{[1-(hydroxymethyl)cyclopropyl]methoxy}-2,3-dihydro-1H-isoindol-1-one;2-[(1R)-1-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-1-{[1-(hydroxymethyl)cyclopropyl]methoxy}-3-oxo-2,3-dihydro-1H-isoindol-5-yl]-2-hydroxy-N,N-dimethylpropanamide;2-[(1R)-1-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-1-{[1-(hydroxymethyl)cyclopropyl]methoxy}-3-oxo-2,3-dihydro-1H-isoindol-5-yl]-2-hydroxy-N-methylpropanamide;(3R)-2-{[4-chloro-2-(methylsulfanyl)phenyl]methyl}-3-(4-chlorophenyl)-4-fluoro-3-{[1-(hydroxymethyl)cyclopropyl]methoxy}-6-(2-hydroxypropan-2-yl)-2,3-dihydro-1H-isoindol-1-one;(3R)-2-[(4-chloro-2-methanesulfinylphenyl)methyl]-3-(4-chlorophenyl)-4-fluoro-3-{[1-(hydroxymethyl)cyclopropyl]methoxy}-6-(2-hydroxypropan-2-yl)-2,3-dihydro-1H-isoindol-1-one;(3R)-2-[(4-chloro-2-methanesulfonylphenyl)methyl]-3-(4-chlorophenyl)-4-fluoro-6-(2-hydroxy-1-methoxypropan-2-yl)-3-{[1-(hydroxymethyl)cyclopropyl]methoxy}-2,3-dihydro-1H-isoindol-1-one;(3R)-2-[(4-chloro-2-methanesulfonylphenyl)methyl]-3-(4-chlorophenyl)-6-(1,2-dihydroxypropan-2-yl)-4-fluoro-3-{[1-(hydroxymethyl)cyclopropyl]methoxy}-2,3-dihydro-1H-isoindol-1-one;(3R)-2-[(4-chloro-2-methanesulfonylphenyl)methyl]-3-(4-chlorophenyl)-4-fluoro-6-[2-hydroxy-1-(4-methylpiperazin-1-yl)propan-2-yl]-3-[(3R)-oxolan-3-yloxy]-2,3-dihydro-1H-isoindol-1-one;(3R)-2-[(4-chloro-2-methanesulfonylphenyl)methyl]-3-(4-chlorophenyl)-4-fluoro-6-[2-hydroxy-1-(4-methylpiperazin-1-yl)propan-2-yl]-3-[(3S)-oxolan-3-yloxy]-2,3-dihydro-1H-isoindol-1-one;(3S)-3-(4-chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-(2-hydroxypropan-2-yl)-3-oxo-1-[(3S)-oxolan-3-yloxy]-2,3-dihydro-1H-isoindol-2-yl]propanoicacid;1-({[(1R)-2-{[4-chloro-2-(hydroxymethyl)phenyl]methyl}-1-(4-chlorophenyl)-7-fluoro-5-(2-hydroxypropan-2-yl)-3-oxo-2,3-dihydro-1H-isoindol-1-yl]oxy}methyl)cyclopropane-1-carbonitrile;1-({[(1R)-2-[(4-chloro-2-methanesulfonylphenyl)methyl]-1-(4-chlorophenyl)-7-fluoro-5-[1-hydroxy-1-(1-methyl-1H-pyrazol-4-yl)ethyl]-3-oxo-2,3-dihydro-1H-isoindol-1-yl]oxy}methyl)cyclopropane-1-carboxamide;(3R)-2-[(4-chloro-2-methanesulfonylphenyl)methyl]-3-(4-chlorophenyl)-4-fluoro-6-[1-hydroxy-1-(1-methyl-1H-pyrazol-4-yl)ethyl]-3-[(1-hydroxycyclopropyl)methoxy]-2,3-dihydro-1H-isoindol-1-one;(3R)-2-[(4-chloro-2-methanesulfonylphenyl)methyl]-3-(4-chlorophenyl)-4-fluoro-6-[2-hydroxy-1-(4-methylpiperazin-1-yl)propan-2-yl]-3-{[1-(hydroxymethyl)cyclopropyl]methoxy}-2,3-dihydro-1H-isoindol-1-one;5-chloro-2-{[(1R)-1-(4-chlorophenyl)-1-[(1-cyanocyclopropyl)methoxy]-7-fluoro-5-(2-hydroxypropan-2-yl)-3-oxo-2,3-dihydro-1H-isoindol-2-yl]methyl}benzoicacid;(3R)-2-[(4-chloro-2-methanesulfonylphenyl)methyl]-3-(4-chlorophenyl)-4-fluoro-6-[1-hydroxy-1-(1-methylpiperidin-4-yl)ethyl]-3-{[1-(hydroxymethyl)cyclopropyl]methoxy}-2,3-dihydro-1H-isoindol-1-one;(3R)-2-{[4-chloro-2-(dimethylphosphoryl)phenyl]methyl}-3-(4-chlorophenyl)-4-fluoro-3-{[1-(hydroxymethyl)cyclopropyl]methoxy}-6-(2-hydroxypropan-2-yl)-2,3-dihydro-1H-isoindol-1-one;(3R)-2-[(4-chloro-2-methanesulfonylphenyl)methyl]-3-(4-chlorophenyl)-4-fluoro-6-[hydroxy(oxan-4-yl)methyl]-3-{[1-(hydroxymethyl)cyclopropyl]methoxy}-2,3-dihydro-1H-isoindol-1-one;1-({[(1R)-2-[(4-chloro-2-methanesulfonylphenyl)methyl]-1-(4-chlorophenyl)-7-fluoro-5-[1-hydroxy-1-(oxan-4-yl)ethyl]-3-oxo-2,3-dihydro-1H-isoindol-1-yl]oxy}methyl)cyclopropane-1-carboxamide;5-chloro-2-{[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[1-hydroxy-1-(1-methylpiperidin-4-yl)ethyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]methyl}benzoicacid;(3S)-3-(4-chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[1-hydroxy-1-(oxan-4-yl)ethyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]propanoicacid;4-[(1R)-1-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[1-hydroxy-1-(1-methyl-1H-imidazol-4-yl)propyl]-3-oxo-1-[(3S)-oxolan-3-yloxy]-2,3-dihydro-1H-isoindol-2-yl]-2-hydroxyethyl]benzonitrile;4-{[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[1-hydroxy-1-(1-methyl-1H-imidazol-4-yl)propyl]-3-oxo-1-[(3S)-oxolan-3-yloxy]-2,3-dihydro-1H-isoindol-2-yl]methyl}-3-(hydroxymethyl)benzonitrile;4-{[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[1-hydroxy-1-(1-methyl-1H-imidazol-4-yl)propyl]-1-{[1-(hydroxymethyl)cyclopropyl]methoxy}-3-oxo-2,3-dihydro-1H-isoindol-2-yl]methyl}benzonitrile;4-{[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[1-hydroxy-1-(1-methyl-1H-imidazol-4-yl)propyl]-3-oxo-1-[(3S)-oxolan-3-yloxy]-2,3-dihydro-1H-isoindol-2-yl]methyl}benzonitrile;(3S)-3-(4-chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[1-(4-fluorooxan-4-yl)-1-hydroxyethyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]propanoicacid;(4S)-4-(4-chlorophenyl)-4-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[1-hydroxy-1-(1-methyl-1H-pyrazol-3-yl)propyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]butanoicacid;(3S)-3-(4-chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[1-(4-fluorooxan-4-yl)-1-hydroxypropyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]propanoicacid;(3S)-3-(4-chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-5-(1-cyclobutyl-1-hydroxyethyl)-7-fluoro-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]propanoicacid;(3S)-3-(4-chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[(1S)-1-hydroxy-1-(oxan-4-yl)propyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]propanoicacid;(3S)-3-(4-chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[(1R)-1-hydroxy-1-(oxan-4-yl)propyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]propanoicacid;(4S)-4-(4-chlorophenyl)-4-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[(1S)-1-hydroxy-1-(oxan-4-yl)propyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]butanoicacid;(4S)-4-(4-chlorophenyl)-4-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[(1R)-1-hydroxy-1-(oxan-4-yl)propyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]butanoicacid;(4S)-4-(4-Chlorophenyl)-4-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[(1R)-1-(4-fluorooxan-4-yl)-1-hydroxypropyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]butanoicacid;(3S)-3-(4-chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[(1R)-1-(4-fluorooxan-4-yl)-1-hydroxypropyl]-1-trideuteromethoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]propanoicacid;(3S)-3-(4-chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-1-ethoxy-7-fluoro-5-[(1R)-1-(4-fluorooxan-4-yl)-1-hydroxypropyl]-3-oxo-2,3-dihydro-1H-isoindol-2-yl]propanoicacid;(4S)-4-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[(1R)-1-(4-fluorooxan-4-yl)-1-hydroxypropyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]-4-(4-methoxyphenyl)butanoicacid;(4S)-4-(4-chlorophenyl)-4-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-{1-hydroxy-1-[trans-4-hydroxycyclohexyl]propyl}-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]butanoicacid;2-(5-chloro-2-{[1-(4-chlorophenyl)-7-fluoro-5-[(1R)-1-(4-fluorooxan-4-yl)-1-hydroxypropyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]methyl}phenoxy)aceticacid;5-chloro-2-{[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[(1S)-1-hydroxy-1-(oxan-4-yl)propyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]methyl}benzoicacid;5-chloro-2-{[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[(1R)-1-hydroxy-1-(oxan-4-yl)propyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]methyl}benzoicacid;5-chloro-2-{[(1R)-1-(4-chlorophenyl)-1-ethoxy-7-fluoro-5-[(1S)-1-hydroxy-1-(oxan-4-yl)propyl]-3-oxo-2,3-dihydro-1H-isoindol-2-yl]methyl}benzoicacid;2-{[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[(1R)-1-(4-fluorooxan-4-yl)-1-hydroxypropyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]methyl}-5-methylbenzoicacid;2-{[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[(1R)-1-(4-fluorooxan-4-yl)-1-hydroxypropyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]methyl}-5-methoxybenzoicacid;2-(5-chloro-2-{[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[(1S)-1-hydroxy-1-(oxan-4-yl)propyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]methyl}phenyl)-2-methylpropanoicacid;2-(5-chloro-2-{[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[(1S)-1-hydroxy-1-(oxan-4-yl)propyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]methyl}phenyl)aceticacid;2-(5-chloro-2-{[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[(1R)-1-hydroxy-1-(oxan-4-yl)propyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]methyl}phenyl)aceticacid;(2S,3S)-3-(4-chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[(1S)-1-hydroxy-1-(oxan-4-yl)propyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]-2-methylpropanoicacid;(3S)-3-(4-chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-7-fluoro-1-[(3-fluorooxetan-3-yl)methoxy]-5-(2-hydroxybutan-2-yl)-3-oxo-2,3-dihydro-1H-isoindol-2-yl]propanoicacid;(3S)-3-(4-chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[1-hydroxy-1-(pyridin-2-yl)propyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]propanoicacid;(3R)-2-[(4-chloro-2-methanesulfonylphenyl)methyl]-3-(4-chlorophenyl)-4-fluoro-6-[1-(4-fluoropiperidin-4-yl)-1-hydroxypropyl]-3-methoxy-2,3-dihydro-1H-isoindol-1-one;4-{[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[(1S)-1-hydroxy-1-(1-methylpiperidin-4-yl)propyl]-3-oxo-1-[cis-3-hydroxycyclobutoxy]-2,3-dihydro-1H-isoindol-2-yl]methyl}benzonitrile;(3S)-3-(4-chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[1-(4-fluoro-1-methylpiperidin-4-yl)-1-hydroxypropyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]propanoicacid; tert-butyl2-{4-[(1S)-1-[(1R)-1-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-7-fluoro-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-5-yl]-1-hydroxypropyl]piperidin-1-yl}acetate;tert-butyl2-{4-[(1R)-1-[(1R)-1-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-7-fluoro-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-5-yl]-1-hydroxypropyl]piperidin-1-yl}acetate;2-{4-[(1S)-1-[(1R)-1-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-7-fluoro-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-5-yl]-1-hydroxypropyl]piperidin-1-yl}aceticacid;2-{4-[(1R)-1-[(1R)-1-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-7-fluoro-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-5-yl]-1-hydroxypropyl]piperidin-1-yl}aceticacid; methyl3-{4-[(1S)-1-[(1R)-1-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-7-fluoro-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-5-yl]-1-hydroxypropyl]piperidin-1-yl}propanoate;and3-{4-[(1S)-1-[(1R)-1-(4-chlorophenyl)-2-[(4-chlorophenyl)methyl]-7-fluoro-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-5-yl]-1-hydroxypropyl]piperidin-1-yl}propanoicacid.
 24. A compound according to claim 1, or a tautomer, N-oxide,pharmaceutically acceptable salt or solvate thereof, wherein thecompound is selected from:(2S,3S)-3-(4-chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[(1S)-1-hydroxy-1-(oxan-4-yl)propyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]-2-methylpropanoicacid;(3S)-3-(4-chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[1-hydroxy-1-(oxan-4-yl)ethyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]propanoicacid;2-(5-chloro-2-{[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[(1S)-1-hydroxy-1-(oxan-4-yl)propyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]methyl}phenyl)-2-methylpropanoicacid; and4-{[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[1-hydroxy-1-(1-methyl-1H-imidazol-4-yl)propyl]-1-{[1-(hydroxymethyl)cyclopropyl]methoxy}-3-oxo-2,3-dihydro-1H-isoindol-2-yl]methyl}benzonitrile.25. A combination comprising a compound of formula (I) as defined inclaim 1, or a tautomer or a solvate or a pharmaceutically acceptablesalt thereof, with one or more other therapeutic agents (e.g. anticanceragents).
 26. A combination according to claim 25, wherein the one ormore other therapeutic agents are selected from groups (i) to (xlix) asdefined herein.
 27. A pharmaceutical composition comprising a compoundof formula (I) as defined in claim 1, or a tautomer or a solvate or apharmaceutically acceptable salt thereof.
 28. A pharmaceuticalcomposition comprising a compound of formula (I) as defined in claim 1,or a tautomer or a solvate or a pharmaceutically acceptable saltthereof, one or more other therapeutic agents (e.g. anticancer agents),and a pharmaceutically acceptable carrier.
 29. (canceled)
 30. (canceled)31. A method for: therapy; treatment of a disease state or conditionmediated by MDM2-p53; treatment of a disease state or condition asdescribed herein; treatment of cancer; or treatment of cancer, whereinthe compound is used in combination with one or more other compounds ortherapies, said method comprising administering to a patient a compoundas defined in claim 1, or a tautomer or a solvate or a pharmaceuticallyacceptable salt thereof.
 32. A method of inhibiting the interaction ofp53 with MDM2 in a subject, the method comprising administering to thesubject a compound as defined in claim 1, or a tautomer or a solvate ora pharmaceutically acceptable salt thereof.
 33. A process for thepreparation of a compound of formula (I) as defined in claim 1, or atautomer, stereoisomer, N-oxide, pharmaceutically acceptable salt, orsolvate thereof which comprises: (a) reacting a compound of formula(VIII) with an organometallic reagent of the formula R⁷M (where M is ametal), for example a Grignard reagent of the formula R⁷MgBr:

wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, a, s m and n are as defined in claim1; (b) interconversion of a compound of formula (I) or protectedderivative thereof to a further compound of formula (I) or protectedderivative thereof; and/or (c) deprotection of a protected derivative ofa compound of formula (I); and/or (d) providing a compound of formula(I) and forming a pharmaceutically acceptable salt of the compound.